chr17-31116596-A-G

Variant names:

• chr17-31116596-A-G
• rs12948444
• NM_001042492.3:c.60+21227A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042492.3(NF1):​c.60+21227A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,988 control chromosomes in the GnomAD database, including 25,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (25969 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.479
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.60+21227A>G		intron_variant	Intron 1 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.60+21227A>G		intron_variant	Intron 1 of 56		NP_000258.1
NF1	NM_001128147.3	c.60+21227A>G		intron_variant	Intron 1 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.60+21227A>G		intron_variant	Intron 1 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82194 AN: 151870 Hom.: 25968 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.611

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82217 AN: 151988 Hom.: 25969 Cov.: 31 AF XY: 0.539 AC XY: 40051 AN XY: 74292

African (AFR) AF: 0.196 AC: 8123 AN: 41456

American (AMR) AF: 0.555 AC: 8476 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3468

East Asian (EAS) AF: 0.566 AC: 2927 AN: 5168

South Asian (SAS) AF: 0.644 AC: 3106 AN: 4820

European-Finnish (FIN) AF: 0.655 AC: 6899 AN: 10534

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47853 AN: 67956

Other (OTH) AF: 0.611 AC: 1289 AN: 2108

Alfa AF: 0.612 Hom.: 6939

Bravo AF: 0.521

Asia WGS AF: 0.580 AC: 2014 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.3
DANN	Benign	0.58
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs12948444; hg19: chr17-29443614;