17-31095311-T-G

Variant names:

• chr17-31095311-T-G
• rs886041346
• NM_001042492.3:c.2T>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000144 in 1,385,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.51
• Publications: 31 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]

MIR4733HG (HGNC:55332): (MIR4733 host gene)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 117 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 31156124. Lost 0.024 part of the original CDS.
• PS1: Another start lost variant in NM_001042492.3 (NF1) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31095311-T-G is Pathogenic according to our data. Variant chr17-31095311-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 426634.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.2T>G	p.Met1?	start_lost	Exon 1 of 57	NP_000258.1
	NF1	NM_001128147.3		c.2T>G	p.Met1?	start_lost	Exon 1 of 15	NP_001121619.1	P21359-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385328 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 683466

⚠️ 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: 31490

American (AMR) AF: 0.00 AC: 0 AN: 35612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1078082

Other (OTH) AF: 0.00 AC: 0 AN: 57680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurofibromatosis, type 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.74
MutPred		0.99		Gain of MoRF binding (P = 6e-04)
MVP		0.75
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		-0.30	Neutral
Varity_R		0.97
gMVP		0.89
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041346; hg19: chr17-29422329;