rs143502927

chr17-31334931-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_001042492.3(NF1):c.5906A>T(p.Gln1969Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1969R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 6.87

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001042492.3
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.19233212).
• BP6: Variant 17-31334931-A-T is Benign according to our data. Variant chr17-31334931-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185913.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4}. Variant chr17-31334931-A-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.5906A>T	p.Gln1969Leu	missense_variant	40/58	ENST00000358273.9
NF1	NM_000267.3	c.5843A>T	p.Gln1948Leu	missense_variant	39/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.5906A>T	p.Gln1969Leu	missense_variant	40/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152002 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251356 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135864

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727178

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152002 Hom.: 0 Cov.: 29 AF XY: 0.000269 AC XY: 20 AN XY: 74236

Gnomad4 AFR AF: 0.000894

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2015	​<span style="background-color:initial">Thep.Q1969L<span style="background-color:initial"> variant (also known as c.5906A>T), located in coding exon 40 of theNF1<span style="background-color:initial"> gene, results from an A to T substitution at nucleotide position 5906. The glutamine at codon 1969 is replaced by leucine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs143502927. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/13006) total alleles studied, having been observed in 0.09% (4/4406) African American alleles. This variant was not reported in the 1000 Genomes Project population-based cohort. To date, this alteration has been detected with an allele frequency of approximately 0.013% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFTin silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.Q1969L remains unclear. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 03, 2021	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.5843A>T, in exon 39 that results in an amino acid change, p.Gln1948Leu. This sequence change does not appear to have been previously described in patients with NF1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.084% in the African/African American subpopulation (dbSNP rs143502927). The p.Gln1948Leu change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. The p.Gln1948Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Gln1948Leu change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2023	Variant summary: NF1 c.5843A>T (p.Gln1948Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251356 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although a pseudogene is present, this region does not have high homology to the pseudogene. p. c.5843A>T has been reported in the literature in an individual with Breast cancer (Guindalini_2022) without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27069254, 10678181, 23460398, 29872168, 35264596, 29089047). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2018

This variant is denoted NF1 c.5843A>T at the cDNA level, p.Gln1948Leu (Q1948L) at the protein level, and results in the change of a Glutamine to a Leucine (CAA>CTA). This variant was observed in one individual undergoing whole exome sequencing, for whom no specific clinical information was provided (Li 2017). NF1 Gln1948Leu was observed at an allele frequency of 0.08% (20/24,020) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Gln1948Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Neurofibromatosis, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2021

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;.;T;.
Eigen	Benign	-0.041
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D;D;D;.
REVEL	Benign	0.29
Sift	Benign	0.23	T;T;T;.
Sift4G	Benign	0.27	T;T;T;.
Polyphen		0.0	B;B;.;.
Vest4		0.60
MVP		0.82
MPC		1.1
ClinPred		0.19	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143502927; hg19: chr17-29661949;