10-100977677-A-G

Variant names:

• chr10-100977677-A-G
• rs779061181
• NM_017893.4:c.382A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017893.4(SEMA4G):​c.382A>G​(p.Thr128Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA4G NM_017893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017893.4. 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.382A>G	p.Thr128Ala	missense	Exon 5 of 15	NP_060363.2
	SEMA4G	NM_001393925.1		c.382A>G	p.Thr128Ala	missense	Exon 5 of 15	NP_001380854.1	Q9NTN9-1
	SEMA4G	NM_001203244.1		c.382A>G	p.Thr128Ala	missense	Exon 4 of 14	NP_001190173.1	Q9NWU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4G	ENST00000210633.4	TSL:1 MANE Select	c.382A>G	p.Thr128Ala	missense	Exon 5 of 15	ENSP00000210633.3	Q9NTN9-2
	SEMA4G	ENST00000517724.5	TSL:1	c.382A>G	p.Thr128Ala	missense	Exon 4 of 14	ENSP00000430175.1	Q9NTN9-3
	SEMA4G	ENST00000521006.5	TSL:1	n.382A>G		non_coding_transcript_exon	Exon 5 of 16	ENSP00000430881.1	Q9NTN9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.061	T
Polyphen		0.88	P
Vest4		0.58
MutPred		0.73		Loss of stability (P = 0.0202)
MVP		0.76
MPC		0.34
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.81
gMVP		0.85
Mutation Taster		=81/19	polymorphism

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: rs779061181; hg19: chr10-102737434;