rs73980038

chr17-19357903-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BS1 BS2

The NM_015681.6(B9D1):c.181C>T(p.Arg61Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,102 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (24 hom.)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.96

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]

ACMG classification

Verdict is Benign. Variant got -14 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
• BP6: Variant 17-19357903-G-A is Benign according to our data. Variant chr17-19357903-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0098 (1492/152252) while in subpopulation AFR AF= 0.0341 (1418/41544). AF 95% confidence interval is 0.0327. There are 24 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B9D1	NM_015681.6	c.181C>T	p.Arg61Trp	missense_variant	3/7	ENST00000261499.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B9D1	ENST00000261499.11	c.181C>T	p.Arg61Trp	missense_variant	3/7	1	NM_015681.6	P1

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1492 AN: 152136 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.000103

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00260 AC: 653 AN: 251442 Hom.: 7 AF XY: 0.00181 AC XY: 246 AN XY: 135900

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000993 AC: 1451 AN: 1461850 Hom.: 24 Cov.: 30 AF XY: 0.000846 AC XY: 615 AN XY: 727224

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152252 Hom.: 24 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74448

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00180 Hom.: 4

Bravo AF: 0.0116

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00309 AC: 375

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Meckel syndrome, type 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0039	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D;D;D;.
Sift	Uncertain	0.012	D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.013	D;.;D;D;D;D;D;.
Polyphen		0.99	.;.;D;.;.;.;.;.
Vest4		0.37
MVP		0.75
MPC		0.56
ClinPred		0.022	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.080
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73980038; hg19: chr17-19261216; COSMIC: COSV99265068; COSMIC: COSV99265068;