rs11190780

Variant names:

• chr10-100984619-T-C
• rs11190780
• ENST00000517724.5:c.1835T>C

Variant summary

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

The NM_001203244.1(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. 13/17 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 0.092 (733 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9091 hom.)
• Consequence: SEMA4G NM_001203244.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119
• Publications: 16 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=0.0012831688).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001203244.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4G	NM_017893.4	MANE Select	c.*488T>C		3_prime_UTR	Exon 15 of 15	NP_060363.2
	SEMA4G	NM_001203244.1		c.1835T>C	p.Met612Thr	missense	Exon 14 of 14	NP_001190173.1	Q9NWU8
	SEMA4G	NM_001393925.1		c.*488T>C		3_prime_UTR	Exon 15 of 15	NP_001380854.1	Q9NTN9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4G	ENST00000517724.5	TSL:1	c.1835T>C	p.Met612Thr	missense	Exon 14 of 14	ENSP00000430175.1	Q9NTN9-3
	SEMA4G	ENST00000210633.4	TSL:1 MANE Select	c.*488T>C		3_prime_UTR	Exon 15 of 15	ENSP00000210633.3	Q9NTN9-2
	MRPL43	ENST00000318325.6	TSL:1	c.466-802A>G		intron	N/A	ENSP00000315364.2	Q8N983-1

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

GnomAD2 exomes AF: 0.0902 AC: 12417 AN: 137600 AF XY: 0.0906

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 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

African (AFR) AF: 0.0627 AC: 1982 AN: 31596

American (AMR) AF: 0.0629 AC: 2244 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3946 AN: 25180

East Asian (EAS) AF: 0.0152 AC: 542 AN: 35738

South Asian (SAS) AF: 0.0699 AC: 5536 AN: 79236

European-Finnish (FIN) AF: 0.0815 AC: 2768 AN: 33958

Middle Eastern (MID) AF: 0.0941 AC: 536 AN: 5696

European-Non Finnish (NFE) AF: 0.121 AC: 130132 AN: 1078924

Other (OTH) AF: 0.110 AC: 6383 AN: 57946

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

African (AFR) AF: 0.0659 AC: 2737 AN: 41538

American (AMR) AF: 0.0836 AC: 1279 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3470

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.0638 AC: 308 AN: 4830

European-Finnish (FIN) AF: 0.0843 AC: 895 AN: 10614

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7905 AN: 68008

Other (OTH) AF: 0.112 AC: 237 AN: 2112

Alfa AF: 0.108 Hom.: 4000

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
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
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.12
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
PromoterAI		0.057	Neutral
Mutation Taster		=98/2	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: rs11190780; hg19: chr10-102744376; COSMIC: COSV52968271; COSMIC: COSV52968271;