10-100984574-A-T

Variant names:

• chr10-100984574-A-T
• rs11591349
• ENST00000517724.5:c.1790A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000517724.5(SEMA4G):​c.1790A>T​(p.Asp597Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,535,904 control chromosomes in the GnomAD database, including 135,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (10772 hom., cov: 33)
  • Exomes 𝑓: 0.42 (124590 hom.)
• Consequence: SEMA4G ENST00000517724.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.833
• Publications: 25 publications found

Genes affected

SEMA4G (HGNC:10735): (semaphorin 4G) Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

MRPL43 (HGNC:14517): (mitochondrial ribosomal protein L43) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. This gene and the gene for a semaphorin class 4 protein (SEMA4G) overlap at map location 10q24.31 and are transcribed in opposite directions. Sequence analysis identified multiple transcript variants encoding at least four different protein isoforms. [provided by RefSeq, Jul 2008]

ENSG00000236662 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3070655E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4G	NM_017893.4	c.*443A>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000210633.4	NP_060363.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4G	ENST00000210633.4	c.*443A>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_017893.4	ENSP00000210633.3

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52559 AN: 151946 Hom.: 10773 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.0684

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.381 AC: 52310 AN: 137164 AF XY: 0.389

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.0650

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.416 AC: 575745 AN: 1383840 Hom.: 124590 Cov.: 64 AF XY: 0.417 AC XY: 284727 AN XY: 682860

African (AFR) AF: 0.120 AC: 3786 AN: 31594

American (AMR) AF: 0.367 AC: 13086 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11452 AN: 25182

East Asian (EAS) AF: 0.0517 AC: 1848 AN: 35734

South Asian (SAS) AF: 0.400 AC: 31692 AN: 79232

European-Finnish (FIN) AF: 0.497 AC: 16865 AN: 33910

Middle Eastern (MID) AF: 0.467 AC: 2658 AN: 5692

European-Non Finnish (NFE) AF: 0.438 AC: 472110 AN: 1078878

Other (OTH) AF: 0.384 AC: 22248 AN: 57920

GnomAD4 genome AF: 0.346 AC: 52554 AN: 152064 Hom.: 10772 Cov.: 33 AF XY: 0.348 AC XY: 25835 AN XY: 74316

African (AFR) AF: 0.138 AC: 5709 AN: 41492

American (AMR) AF: 0.398 AC: 6083 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3470

East Asian (EAS) AF: 0.0686 AC: 355 AN: 5176

South Asian (SAS) AF: 0.393 AC: 1895 AN: 4820

European-Finnish (FIN) AF: 0.484 AC: 5119 AN: 10568

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30374 AN: 67938

Other (OTH) AF: 0.374 AC: 787 AN: 2106

Alfa AF: 0.412 Hom.: 8240

Bravo AF: 0.325

TwinsUK AF: 0.433 AC: 1604

ALSPAC AF: 0.422 AC: 1628

ExAC AF: 0.281 AC: 6795

Asia WGS AF: 0.227 AC: 791 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.00063	T;T
MetaSVM	Benign	-0.91	T
PhyloP100		0.83
PROVEAN	Benign	0.77	N;.
REVEL	Benign	0.011
Sift	Uncertain	0.010	D;.
Sift4G	Benign	0.29	T;.
Vest4		0.45
ClinPred		0.0077	T
GERP RS		2.5
PromoterAI		-0.0037	Neutral
Mutation Taster		=91/9	polymorphism (auto)

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: rs11591349; hg19: chr10-102744331; COSMIC: COSV52966527; COSMIC: COSV52966527;