19-4543953-C-G

Position:

• chr19-4543953-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032108.4(SEMA6B):​c.2315G>C​(p.Gly772Ala) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G772S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.375

Genes affected

SEMA6B (HGNC:10739): (semaphorin 6B) This gene encodes a member of the semaphorin family, a group of proteins characterized by the presence of a conserved semaphorin (sema) domain. Whereas some semaphorins are transmembrane proteins, others are secreted. Semaphorins play a major role in axon guidance. The protein encoded by this gene may be involved in both peripheral and central nervous system development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03888136).
• BP6: Variant 19-4543953-C-G is Benign according to our data. Variant chr19-4543953-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2534537.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA6B	NM_032108.4	c.2315G>C	p.Gly772Ala	missense_variant	17/17	ENST00000586582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA6B	ENST00000586582.6	c.2315G>C	p.Gly772Ala	missense_variant	17/17	1	NM_032108.4	P1
SEMA6B	ENST00000586965.1	c.1851+464G>C		intron_variant		1
SEMA6B	ENST00000676793.1	c.2315G>C	p.Gly772Ala	missense_variant	17/17			P1
SEMA6B	ENST00000677828.1	c.*1577G>C		3_prime_UTR_variant, NMD_transcript_variant	17/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.033
DANN	Benign	0.64
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.18		Loss of sheet (P = 0.0054);
MVP		0.043
MPC		1.8
ClinPred		0.12	T
GERP RS		-5.6
Varity_R		0.035
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4543965;