rs11190780

Positions:

• chr10-100984619-T-C

Variant summary

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

The ENST00000517724.5(SEMA4G):​c.1835T>C​(p.Met612Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,536,230 control chromosomes in the GnomAD database, including 9,824 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 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 0.092 (733 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9091 hom.)
• Consequence: SEMA4G ENST00000517724.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012831688).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4G	NM_017893.4	c.*488T>C		3_prime_UTR_variant	15/15	ENST00000210633.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4G	ENST00000210633.4	c.*488T>C		3_prime_UTR_variant	15/15	1	NM_017893.4	P4
	ENST00000447344.1	n.168+828A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0924 AC: 14060 AN: 152138 Hom.: 733 Cov.: 33

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0837

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0902 AC: 12417 AN: 137600 Hom.: 661 AF XY: 0.0906 AC XY: 6758 AN XY: 74606

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0252

Gnomad SAS exome AF: 0.0698

Gnomad FIN exome AF: 0.0797

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.111 AC: 154069 AN: 1383974 Hom.: 9091 Cov.: 35 AF XY: 0.111 AC XY: 75507 AN XY: 682934

Gnomad4 AFR exome AF: 0.0627

Gnomad4 AMR exome AF: 0.0629

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.0699

Gnomad4 FIN exome AF: 0.0815

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.0924 AC: 14071 AN: 152256 Hom.: 733 Cov.: 33 AF XY: 0.0887 AC XY: 6600 AN XY: 74440

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.0836

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.0638

Gnomad4 FIN AF: 0.0843

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.112

Alfa AF: 0.112 Hom.: 2231

Bravo AF: 0.0932

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.123 AC: 474

ExAC AF: 0.0442 AC: 2014

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.6
DANN	Benign	0.63
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.22	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.60	N;.
REVEL	Benign	0.014
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0050	D;.
Vest4		0.11
ClinPred		0.0044	T
GERP RS		1.4

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: rs11190780; hg19: chr10-102744376; COSMIC: COSV52968271; COSMIC: COSV52968271;