19-4543875-C-T

Variant names:

• chr19-4543875-C-T
• rs1045115813
• NM_032108.4:c.2393G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_032108.4(SEMA6B):​c.2393G>A​(p.Arg798Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000474 in 1,054,882 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: 0.0000047 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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=0.14718261).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6B	NM_032108.4	c.2393G>A	p.Arg798Gln	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.2393G>A	p.Arg798Gln	missense_variant	Exon 17 of 17	1	NM_032108.4	ENSP00000467290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000474 AC: 5 AN: 1054882 Hom.: 0 Cov.: 33 AF XY: 0.00000603 AC XY: 3 AN XY: 497822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000553

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

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2393G>A (p.R798Q) alteration is located in exon 17 (coding exon 16) of the SEMA6B gene. This alteration results from a G to A substitution at nucleotide position 2393, causing the arginine (R) at amino acid position 798 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	Pathogenic	0.66
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.92	D
Sift4G	Benign	0.094	T
Polyphen		0.14	B
Vest4		0.078
MutPred		0.17		Loss of loop (P = 0.0022);
MVP		0.043
MPC		3.4
ClinPred		0.67	D
GERP RS		1.9
Varity_R		0.16
gMVP		0.61

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: rs1045115813; hg19: chr19-4543887;