17-31338704-G-T

Variant names:

• chr17-31338704-G-T
• rs1555535023
• NM_001042492.3:c.6820G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.6820G>T​(p.Ala2274Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2274G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.59
• Publications: 0 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-31338704-G-T is Pathogenic according to our data. Variant chr17-31338704-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 527433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.6820G>T	p.Ala2274Ser	missense splice_region	Exon 46 of 58	NP_001035957.1
	NF1	NM_000267.4		c.6757G>T	p.Ala2253Ser	missense splice_region	Exon 45 of 57	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.6820G>T	p.Ala2274Ser	missense splice_region	Exon 46 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6757G>T	p.Ala2253Ser	missense splice_region	Exon 45 of 57	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1985G>T		splice_region non_coding_transcript_exon	Exon 46 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456600 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107496

Other (OTH) AF: 0.00 AC: 0 AN: 60228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.058
Sift	Benign	0.071	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.25
MutPred		0.45		Gain of disorder (P = 0.0284)
MVP		0.61
MPC		1.0
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.25
gMVP		0.37
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: 0

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

Other links and lift over

dbSNP: rs1555535023; hg19: chr17-29665722;