chr2-74656612-A-G

Variant names:

• chr2-74656612-A-G
• rs1257734830
• NM_004263.5:c.224A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004263.5(SEMA4F):​c.224A>G​(p.His75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SEMA4F NM_004263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066726774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004263.5. 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
	SEMA4F	NM_004263.5	MANE Select	c.224A>G	p.His75Arg	missense	Exon 2 of 14	NP_004254.2
	SEMA4F	NM_001271662.2		c.224A>G	p.His75Arg	missense	Exon 2 of 13	NP_001258591.1
	SEMA4F	NM_001271661.2		c.224A>G	p.His75Arg	missense	Exon 2 of 10	NP_001258590.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4F	ENST00000357877.7	TSL:1 MANE Select	c.224A>G	p.His75Arg	missense	Exon 2 of 14	ENSP00000350547.2
	SEMA4F	ENST00000339773.9	TSL:1	c.224A>G	p.His75Arg	missense	Exon 2 of 10	ENSP00000342675.5
	SEMA4F	ENST00000420077.5	TSL:1	n.224A>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000416490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251496 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.050	N
PhyloP100		1.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.075
Sift	Benign	0.49	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.30
MutPred		0.51		Loss of catalytic residue at L77 (P = 0.0761)
MVP		0.15
MPC		0.28
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.59
Mutation Taster		=88/12	polymorphism

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: rs1257734830; hg19: chr2-74883739;