rs4919510

Positions:

• chr10-100975021-C-G
• chr10-100975021-C-T

Variant summary

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

The NM_017893.4(SEMA4G):​c.336+1412C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 533,066 control chromosomes in the GnomAD database, including 19,713 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6674 hom., cov: 32)
  • Exomes 𝑓: 0.24 (13039 hom.)
• Consequence: SEMA4G NM_017893.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248

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]

MIR608 (HGNC:32864): (microRNA 608) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA4G	NM_017893.4	c.336+1412C>G		intron_variant		ENST00000210633.4	NP_060363.2
MIR608	NR_030339.1	n.37C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA4G	ENST00000210633.4	c.336+1412C>G		intron_variant		1	NM_017893.4	ENSP00000210633	P4
MIR608	ENST00000384820.1	n.37C>G		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41775 AN: 151862 Hom.: 6659 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.266 AC: 66088 AN: 248610 Hom.: 10406 AF XY: 0.258 AC XY: 34791 AN XY: 134640

Gnomad AFR exome AF: 0.405

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.545

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.242 AC: 92334 AN: 381086 Hom.: 13039 Cov.: 0 AF XY: 0.241 AC XY: 52325 AN XY: 217022

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.545

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.275 AC: 41829 AN: 151980 Hom.: 6674 Cov.: 32 AF XY: 0.277 AC XY: 20573 AN XY: 74288

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.256

Alfa AF: 0.211 Hom.: 1221

Bravo AF: 0.293

Asia WGS AF: 0.413 AC: 1434 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.6
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4919510; hg19: chr10-102734778;