rs4924987

Positions:

• chr17-19343762-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001321215.3(B9D1):​c.500C>T​(p.Pro167Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,613,886 control chromosomes in the GnomAD database, including 453,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (30917 hom., cov: 33)
  • Exomes 𝑓: 0.73 (422413 hom.)
• Consequence: B9D1 NM_001321215.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.254

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.1532996E-7).
• BP6: Variant 17-19343762-G-A is Benign according to our data. Variant chr17-19343762-G-A is described in ClinVar as [Benign]. Clinvar id is 260675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-19343762-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B9D1	NM_015681.6	c.472+28C>T		intron_variant		ENST00000261499.11	NP_056496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B9D1	ENST00000261499.11	c.472+28C>T		intron_variant		1	NM_015681.6	ENSP00000261499.4

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85823 AN: 152014 Hom.: 30924 Cov.: 33

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.00637

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.623

GnomAD3 exomes AF: 0.600 AC: 150429 AN: 250814 Hom.: 54941 AF XY: 0.612 AC XY: 82967 AN XY: 135636

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.00251

Gnomad SAS exome AF: 0.378

Gnomad FIN exome AF: 0.786

Gnomad NFE exome AF: 0.810

Gnomad OTH exome AF: 0.691

GnomAD4 exome AF: 0.734 AC: 1072426 AN: 1461754 Hom.: 422413 Cov.: 79 AF XY: 0.728 AC XY: 529033 AN XY: 727176

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.836

Gnomad4 EAS exome AF: 0.00322

Gnomad4 SAS exome AF: 0.392

Gnomad4 FIN exome AF: 0.792

Gnomad4 NFE exome AF: 0.813

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.564 AC: 85810 AN: 152132 Hom.: 30917 Cov.: 33 AF XY: 0.553 AC XY: 41140 AN XY: 74362

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.843

Gnomad4 EAS AF: 0.00657

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.778

Gnomad4 NFE AF: 0.809

Gnomad4 OTH AF: 0.616

Alfa AF: 0.726 Hom.: 12185

Bravo AF: 0.533

TwinsUK AF: 0.812 AC: 3010

ALSPAC AF: 0.802 AC: 3090

ESP6500AA AF: 0.195 AC: 860

ESP6500EA AF: 0.807 AC: 6938

ExAC AF: 0.597 AC: 72454

Asia WGS AF: 0.170 AC: 593 AN: 3478

EpiCase AF: 0.807

EpiControl AF: 0.799

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Meckel syndrome, type 9 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Joubert syndrome 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.48
DANN	Benign	0.39
FATHMM_MKL	Benign	0.082	N
MetaRNN	Benign	9.2e-7	T;T
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.32	T;.
Vest4		0.045
GERP RS		-0.60

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: rs4924987; hg19: chr17-19247075; COSMIC: COSV52069237; COSMIC: COSV52069237;