2-74662775-G-A

Variant names:

• chr2-74662775-G-A
• rs778626481
• NM_004263.5:c.500G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004263.5(SEMA4F):​c.500G>A​(p.Arg167Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SEMA4F NM_004263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4F	NM_004263.5	c.500G>A	p.Arg167Gln	missense_variant	Exon 5 of 14	ENST00000357877.7	NP_004254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4F	ENST00000357877.7	c.500G>A	p.Arg167Gln	missense_variant	Exon 5 of 14	1	NM_004263.5	ENSP00000350547.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251474 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727172

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33478

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.0000928 AC: 8 AN: 86252

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53406

Gnomad4 NFE exome AF: 0.00000630 AC: 7 AN: 1111904

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500G>A (p.R167Q) alteration is located in exon 5 (coding exon 5) of the SEMA4F gene. This alteration results from a G to A substitution at nucleotide position 500, causing the arginine (R) at amino acid position 167 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.062	T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.56
MutPred		0.65		Loss of methylation at R167 (P = 0.0223);.;.;
MVP		0.19
MPC		0.90
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.59
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs778626481; hg19: chr2-74889902; COSMIC: COSV60284918;