10-100984574-A-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001203244.1(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. 10/14 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 NM_001203244.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.833

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

Verdict is Benign. Variant got -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

GnomAD3 exomes AF: 0.381 AC: 52310 AN: 137164 Hom.: 11002 AF XY: 0.389 AC XY: 28927 AN XY: 74446

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 SAS exome AF: 0.400

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

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.0517

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.384

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

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.0686

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.484

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.374

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
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
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

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