rs771997194

chr17-19360343-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_015681.6(B9D1):c.109G>A(p.Gly37Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

B9D1
NM_015681.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.18

Variant links:

Genes affected

B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]

B9D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a chain B9 domain-containing protein 1 (size 203) in uniprot entity B9D1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_015681.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B9D1	NM_015681.6 linkuse as main transcript	c.109G>A	p.Gly37Ser	missense_variant	2/7	ENST00000261499.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B9D1	ENST00000261499.11 linkuse as main transcript	c.109G>A	p.Gly37Ser	missense_variant	2/7	1	NM_015681.6	P1	Q9UPM9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250784

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 37 of the B9D1 protein (p.Gly37Ser). This variant is present in population databases (rs771997194, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of B9D1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 241064). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

B9D1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

The B9D1 c.109G>A variant is predicted to result in the amino acid substitution p.Gly37Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-19263656-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.020

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.2

D;.;D;D;D;D;D;.

Sift

Uncertain

0.014

D;.;D;D;D;D;D;.

Sift4G

Uncertain

0.018

D;.;D;D;D;D;D;.

Polyphen

0.57

.;.;P;.;.;.;.;.

Vest4

0.70

MutPred

0.91

Gain of catalytic residue at G37 (P = 0.0387);Gain of catalytic residue at G37 (P = 0.0387);Gain of catalytic residue at G37 (P = 0.0387);Gain of catalytic residue at G37 (P = 0.0387);Gain of catalytic residue at G37 (P = 0.0387);Gain of catalytic residue at G37 (P = 0.0387);.;Gain of catalytic residue at G37 (P = 0.0387);

MVP

0.92

MPC

0.64

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.64

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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