chr17-19337749-C-G

Position:

• chr17-19337749-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BS1_Supporting BS2

The ENST00000671102.1(B9D1):​c.536-1G>C variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,534,642 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (30 hom.)
• Consequence: B9D1 ENST00000671102.1 splice_acceptor
• Scores: Splicing: ADA: 0.00006013
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:4
• Conservation: PhyloP100: 0.267

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 5.4131207 fraction of the gene.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1625/152298) while in subpopulation AFR AF= 0.0355 (1476/41552). AF 95% confidence interval is 0.034. There are 23 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B9D1	NM_001321218.2	c.473-1G>C		splice_acceptor_variant
B9D1	NM_001321219.2	c.405-1G>C		splice_acceptor_variant
B9D1	NM_001368769.2	c.113-1G>C		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B9D1	ENST00000582857.2	c.113-1G>C		splice_acceptor_variant		4
B9D1	ENST00000671102.1	c.536-1G>C		splice_acceptor_variant
B9D1	ENST00000674596.1	c.303-1G>C		splice_acceptor_variant
B9D1	ENST00000675510.1	c.405-1G>C		splice_acceptor_variant

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1618 AN: 152180 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00284 AC: 382 AN: 134390 Hom.: 4 AF XY: 0.00201 AC XY: 147 AN XY: 73236

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00157

Gnomad EAS exome AF: 0.0000952

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000720

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00154 AC: 2135 AN: 1382344 Hom.: 30 Cov.: 31 AF XY: 0.00134 AC XY: 914 AN XY: 682074

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.00350

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000884

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.0107 AC: 1625 AN: 152298 Hom.: 23 Cov.: 32 AF XY: 0.0100 AC XY: 748 AN XY: 74460

Gnomad4 AFR AF: 0.0355

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00581 Hom.: 2

Bravo AF: 0.0123

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00221 AC: 38

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -

Joubert syndrome 27 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 26, 2019

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 18, 2023

The c.473-1G>C variant in B9D1 is classified as benign because it has been identified in 3.5% (1469/41430) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). ACMG/AMP Criteria applied: BA1. -

B9D1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.8
DANN	Benign	0.52
FATHMM_MKL	Benign	0.096	N
MutationTaster	Benign	1.0	N
GERP RS		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs73980009; hg19: chr17-19241062;