19-4543752-G-T

Variant names:

• chr19-4543752-G-T
• rs965407880
• NM_032108.4:c.2516C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032108.4(SEMA6B):​c.2516C>A​(p.Pro839Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000931 in 1,074,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18882963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6B	NM_032108.4	c.2516C>A	p.Pro839Gln	missense_variant	Exon 17 of 17	ENST00000586582.6	NP_115484.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6B	ENST00000586582.6	c.2516C>A	p.Pro839Gln	missense_variant	Exon 17 of 17	1	NM_032108.4	ENSP00000467290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.31e-7 AC: 1 AN: 1074144 Hom.: 0 Cov.: 32 AF XY: 0.00000197 AC XY: 1 AN XY: 507200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2516C>A (p.P839Q) alteration is located in exon 17 (coding exon 16) of the SEMA6B gene. This alteration results from a C to A substitution at nucleotide position 2516, causing the proline (P) at amino acid position 839 to be replaced by a glutamine (Q). 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	0.091
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.021	D
Polyphen		0.57	P
Vest4		0.20
MutPred		0.18		Loss of loop (P = 0.0073);
MVP		0.043
MPC		3.0
ClinPred		0.88	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.39

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: rs965407880; hg19: chr19-4543764;