2-74654428-T-C

Variant names:

• chr2-74654428-T-C
• rs530989148
• NM_004263.5:c.52T>C

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.52T>C​(p.Ser18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000512 in 1,562,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SEMA4F NM_004263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.867

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=0.05574447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4F	NM_004263.5	c.52T>C	p.Ser18Pro	missense_variant	Exon 1 of 14	ENST00000357877.7	NP_004254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4F	ENST00000357877.7	c.52T>C	p.Ser18Pro	missense_variant	Exon 1 of 14	1	NM_004263.5	ENSP00000350547.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000603 AC: 1 AN: 165952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000349

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 AF: 0.00000426 AC: 6 AN: 1409984 Hom.: 0 Cov.: 31 AF XY: 0.00000429 AC XY: 3 AN XY: 698868

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 29912

Gnomad4 AMR exome AF: 0.0000248 AC: 1 AN: 40242

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24996

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35086

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 80630

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 43544

Gnomad4 NFE exome AF: 0.00000458 AC: 5 AN: 1092494

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58432

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74470

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000654 AC: 0.0000653509 AN: 0.0000653509

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: 0.0000147 AC: 0.0000147063 AN: 0.0000147063

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52T>C (p.S18P) alteration is located in exon 1 (coding exon 1) of the SEMA4F gene. This alteration results from a T to C substitution at nucleotide position 52, causing the serine (S) at amino acid position 18 to be replaced by a proline (P). 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	0.062
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.56	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.056	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.020	N;.;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.34	T;.;D;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.0010	B;.;B;B;.
Vest4		0.50
MutPred		0.24		Loss of phosphorylation at S18 (P = 0.0344);Loss of phosphorylation at S18 (P = 0.0344);Loss of phosphorylation at S18 (P = 0.0344);Loss of phosphorylation at S18 (P = 0.0344);Loss of phosphorylation at S18 (P = 0.0344);
MVP		0.23
MPC		0.87
ClinPred		0.15	T
GERP RS		1.3
Varity_R		0.18
gMVP		0.41
Mutation Taster		=83/17	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: rs530989148; hg19: chr2-74881555;