rs746022492

Variant names:

• chr17-31232100-A-G
• rs746022492
• NM_001042492.3:c.3225A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-31232100-A-G
• chr17-31232100-A-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001042492.3(NF1):​c.3225A>G​(p.Ala1075Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.135
• 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-31232100-A-G is Benign according to our data. Variant chr17-31232100-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 413021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.135 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3225A>G	p.Ala1075Ala	synonymous_variant	Exon 25 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3225A>G	p.Ala1075Ala	synonymous_variant	Exon 25 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3225A>G	p.Ala1075Ala	synonymous_variant	Exon 25 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245234 AF XY: 0.00000754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.24e-7 AC: 1 AN: 1381164 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 689928

African (AFR) AF: 0.00 AC: 0 AN: 31668

American (AMR) AF: 0.0000229 AC: 1 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 38412

South Asian (SAS) AF: 0.00 AC: 0 AN: 82962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045710

Other (OTH) AF: 0.00 AC: 0 AN: 56858

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 13, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Synonymous alterations with insufficient evidence to classify as benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.70
PhyloP100		0.14
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746022492; hg19: chr17-29559118;