2-74656612-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. 16/23 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

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4F	NM_004263.5	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 14	ENST00000357877.7	NP_004254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4F	ENST00000357877.7	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 14	1	NM_004263.5	ENSP00000350547.2

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

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

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

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

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1112004

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224A>G (p.H75R) alteration is located in exon 2 (coding exon 2) of the SEMA4F gene. This alteration results from a A to G substitution at nucleotide position 224, causing the histidine (H) at amino acid position 75 to be replaced by an arginine (R). 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	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;T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.050	N;.;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.93	N;.;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.49	T;.;T;T;T
Sift4G	Benign	0.12	T;T;D;T;D
Polyphen		0.0010	B;.;B;B;.
Vest4		0.30
MutPred		0.51		Loss of catalytic residue at L77 (P = 0.0761);Loss of catalytic residue at L77 (P = 0.0761);Loss of catalytic residue at L77 (P = 0.0761);Loss of catalytic residue at L77 (P = 0.0761);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

Publications

LitVar

Other links and lift over

dbSNP: rs1257734830; hg19: chr2-74883739;