19-4543963-T-G

Position:

• chr19-4543963-T-G

Variant summary

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

The NM_032108.4(SEMA6B):​c.2305A>C​(p.Thr769Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053625375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA6B	NM_032108.4	c.2305A>C	p.Thr769Pro	missense_variant	17/17	ENST00000586582.6	NP_115484.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA6B	ENST00000586582.6	c.2305A>C	p.Thr769Pro	missense_variant	17/17	1	NM_032108.4	ENSP00000467290	P1
SEMA6B	ENST00000586965.1	c.1851+454A>C		intron_variant		1		ENSP00000465722
SEMA6B	ENST00000676793.1	c.2305A>C	p.Thr769Pro	missense_variant	17/17			ENSP00000503414	P1
SEMA6B	ENST00000677828.1	c.*1567A>C		3_prime_UTR_variant, NMD_transcript_variant	17/17			ENSP00000503277

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.2305A>C (p.T769P) alteration is located in exon 17 (coding exon 16) of the SEMA6B gene. This alteration results from a A to C substitution at nucleotide position 2305, causing the threonine (T) at amino acid position 769 to be replaced by a proline (P). 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	0.047
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.4
DANN	Benign	0.41
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.84	D
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.19		Loss of phosphorylation at T769 (P = 0.0026);
MVP		0.043
MPC		2.1
ClinPred		0.049	T
GERP RS		0.12
Varity_R		0.084
gMVP		0.26

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: rs966035437; hg19: chr19-4543975; COSMIC: COSV56703409; COSMIC: COSV56703409;