19-4543926-C-A

Position:

chr19-4543926-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032108.4(SEMA6B):c.2342G>T(p.Arg781Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,200,806 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 13 hom. )

Consequence

SEMA6B
NM_032108.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.757

Variant links:

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]

SEMA6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063651204).

BP6

Variant 19-4543926-C-A is Benign according to our data. Variant chr19-4543926-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2212749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00448 (676/150840) while in subpopulation NFE AF= 0.00523 (353/67554). AF 95% confidence interval is 0.00478. There are 5 homozygotes in gnomad4. There are 367 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 676 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA6B	NM_032108.4 linkuse as main transcript	c.2342G>T	p.Arg781Leu	missense_variant	17/17	ENST00000586582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA6B	ENST00000586582.6 linkuse as main transcript	c.2342G>T	p.Arg781Leu	missense_variant	17/17	1	NM_032108.4	P1	Q9H3T3-1
SEMA6B	ENST00000586965.1 linkuse as main transcript	c.1851+491G>T		intron_variant		1			Q9H3T3-3
SEMA6B	ENST00000676793.1 linkuse as main transcript	c.2342G>T	p.Arg781Leu	missense_variant	17/17			P1	Q9H3T3-1
SEMA6B	ENST00000677828.1 linkuse as main transcript	c.*1604G>T		3_prime_UTR_variant, NMD_transcript_variant	17/17

Frequencies

GnomAD3 genomes

AF:

0.00448

AC:

676

AN:

150734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00251

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00522

Gnomad OTH

AF:

0.00338

GnomAD3 exomes

AF:

0.00746

AC:

AN:

134

Hom.:

AF XY:

0.0125

AC XY:

AN XY:

show subpopulations

Gnomad NFE exome

AF:

0.00746

GnomAD4 exome

AF:

0.00373

AC:

3918

AN:

1049966

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

1811

AN XY:

495452

show subpopulations

Gnomad4 AFR exome

AF:

0.000462

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.000870

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.0291

Gnomad4 NFE exome

AF:

0.00347

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00448

AC:

676

AN:

150840

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

367

AN XY:

73700

show subpopulations

Gnomad4 AFR

AF:

0.000388

Gnomad4 AMR

AF:

0.00251

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.00523

Gnomad4 OTH

AF:

0.00334

Alfa

AF:

0.00789

Hom.:

Bravo

AF:

0.00255

ExAC

AF:

0.00198

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2021

This alteration is classified as 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

SEMA6B: PP2, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.81

D;N;N

PrimateAI

Pathogenic

0.92

Sift4G

Uncertain

0.010

Polyphen

0.80

Vest4

0.23

MVP

0.068

MPC

3.0

ClinPred

0.18

GERP RS

3.0

Varity_R

0.19

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over