10-100978385-A-G

Variant names:

• chr10-100978385-A-G
• rs769933802
• NM_017893.4:c.526A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017893.4(SEMA4G):​c.526A>G​(p.Ile176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I176F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA4G NM_017893.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13545161).

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.526A>G	p.Ile176Val	missense	Exon 6 of 15	NP_060363.2
	SEMA4G	NM_001393925.1		c.526A>G	p.Ile176Val	missense	Exon 6 of 15	NP_001380854.1	Q9NTN9-1
	SEMA4G	NM_001203244.1		c.526A>G	p.Ile176Val	missense	Exon 5 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.526A>G	p.Ile176Val	missense	Exon 6 of 15	ENSP00000210633.3	Q9NTN9-2
	SEMA4G	ENST00000517724.5	TSL:1	c.526A>G	p.Ile176Val	missense	Exon 5 of 14	ENSP00000430175.1	Q9NTN9-3
	MRPL43	ENST00000318325.6	TSL:1	c.*868T>C		3_prime_UTR	Exon 5 of 5	ENSP00000315364.2	Q8N983-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.87	N
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.20
MutPred		0.57		Loss of sheet (P = 0.1398)
MVP		0.23
MPC		0.21
ClinPred		0.085	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.30
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769933802; hg19: chr10-102738142;