2-74673697-G-A

Variant names:

• chr2-74673697-G-A
• rs375402877
• NM_004263.5:c.691G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004263.5(SEMA4F):​c.691G>A​(p.Val231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SEMA4F NM_004263.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.799

Genes affected

SEMA4F (HGNC:10734): (ssemaphorin 4F) This gene encodes a transmembrane class IV semaphorin family protein, which plays a role in neural development. This gene may be involved in neurogenesis in prostate cancer, the development of neurofibromas, and breast cancer tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05336258).
• BP6: Variant 2-74673697-G-A is Benign according to our data. Variant chr2-74673697-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3159831.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4F	NM_004263.5	c.691G>A	p.Val231Met	missense_variant	Exon 7 of 14	ENST00000357877.7	NP_004254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4F	ENST00000357877.7	c.691G>A	p.Val231Met	missense_variant	Exon 7 of 14	1	NM_004263.5	ENSP00000350547.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251274 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000896 AC: 3 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44714

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26118

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86240

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53408

Gnomad4 NFE exome AF: 0.0000468 AC: 52 AN: 1111938

Gnomad4 Remaining exome AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74332

Gnomad4 AFR AF: 0.000314 AC: 0.000313767 AN: 0.000313767

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654193 AN: 0.0000654193

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588097 AN: 0.0000588097

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 03, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.9
DANN	Benign	0.97
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.38	N;.
REVEL	Benign	0.047
Sift	Benign	0.13	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.055	B;.
Vest4		0.21
MVP		0.040
MPC		0.24
ClinPred		0.012	T
GERP RS		-3.2
Varity_R		0.073
gMVP		0.43
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs375402877; hg19: chr2-74900824; COSMIC: COSV60285334; COSMIC: COSV60285334;