rs3087453

Positions:

• chr19-41355029-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000243578.8(B9D2):​c.215-16C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,569,160 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (33 hom.)
• Consequence: B9D2 ENST00000243578.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.878

Genes affected

B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-41355029-G-C is Benign according to our data. Variant chr19-41355029-G-C is described in ClinVar as [Benign]. Clinvar id is 261880.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 = 0.0125 (1899/152278) while in subpopulation AFR AF= 0.0427 (1774/41532). AF 95% confidence interval is 0.0411. There are 40 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B9D2	NM_030578.4	c.215-16C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000243578.8	NP_085055.2
B9D2	XM_011527349.3	c.215-16C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_011525651.1
B9D2	XM_011527350.3	c.56-16C>G		splice_polypyrimidine_tract_variant, intron_variant			XP_011525652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B9D2	ENST00000243578.8	c.215-16C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_030578.4	ENSP00000243578	P1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1894 AN: 152160 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00301 AC: 560 AN: 186078 Hom.: 11 AF XY: 0.00225 AC XY: 228 AN XY: 101200

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000436

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00124 AC: 1758 AN: 1416882 Hom.: 33 Cov.: 32 AF XY: 0.00105 AC XY: 735 AN XY: 699814

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00225

Gnomad4 ASJ exome AF: 0.000294

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.0125 AC: 1899 AN: 152278 Hom.: 40 Cov.: 32 AF XY: 0.0125 AC XY: 928 AN XY: 74456

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00659 Hom.: 4

Bravo AF: 0.0142

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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_noAF	Benign	-0.87
CADD	Benign	0.53
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3087453; hg19: chr19-41860934;