17-31155970-CT-CTT

Position:

• chr17-31155970-CT-CTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.61-4dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,527,950 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: NF1 NM_001042492.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.175

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 17-31155970-C-CT is Benign according to our data. Variant chr17-31155970-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 1197213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000393 (543/1382646) while in subpopulation AFR AF= 0.0101 (303/30116). AF 95% confidence interval is 0.00913. There are 3 homozygotes in gnomad4_exome. There are 242 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 421 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.61-4dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.61-4dup		splice_polypyrimidine_tract_variant, intron_variant			NP_000258.1
NF1	NM_001128147.3	c.61-4dup		splice_polypyrimidine_tract_variant, intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.61-4dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 420 AN: 145222 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00932

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.0000758

Gnomad OTH AF: 0.00251

GnomAD4 exome AF: 0.000393 AC: 543 AN: 1382646 Hom.: 3 Cov.: 33 AF XY: 0.000352 AC XY: 242 AN XY: 687606

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.0000413

Gnomad4 EAS exome AF: 0.0000821

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000104

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000938

GnomAD4 genome AF: 0.00290 AC: 421 AN: 145304 Hom.: 2 Cov.: 31 AF XY: 0.00304 AC XY: 215 AN XY: 70640

Gnomad4 AFR AF: 0.00932

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000758

Gnomad4 OTH AF: 0.00249

Bravo AF: 0.00358

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NF1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	- -

Neurofibromatosis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs551568608; hg19: chr17-29482988;