10-100978365-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017893.4(SEMA4G):c.506G>A(p.Arg169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: SEMA4G NM_017893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016913354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4G	NM_017893.4	c.506G>A	p.Arg169His	missense_variant	6/15	ENST00000210633.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4G	ENST00000210633.4	c.506G>A	p.Arg169His	missense_variant	6/15	1	NM_017893.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 249562 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134882

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461132 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 726766

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000829

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000740 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.506G>A (p.R169H) alteration is located in exon 5 (coding exon 5) of the SEMA4G gene. This alteration results from a G to A substitution at nucleotide position 506, causing the arginine (R) at amino acid position 169 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.84
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.88	N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.65	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.20, 0.0	.;.;B;.;B
Vest4		0.32, 0.33, 0.34
MVP		0.59
MPC		0.31
ClinPred		0.019	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.50

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: rs201619012; hg19: chr10-102738122;