rs7212549

chr17-19343354-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015681.6(B9D1):c.580T>C(p.Leu194=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,614,074 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (205 hom.)
• Consequence: B9D1 NM_015681.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.148

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-19343354-A-G is Benign according to our data. Variant chr17-19343354-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.148 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
B9D1	NM_015681.6	c.580T>C	p.Leu194=	synonymous_variant	7/7	ENST00000261499.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
B9D1	ENST00000261499.11	c.580T>C	p.Leu194=	synonymous_variant	7/7	1	NM_015681.6	P1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2419 AN: 152080 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0110 AC: 2771 AN: 251414 Hom.: 62 AF XY: 0.0124 AC XY: 1680 AN XY: 135888

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0143

Gnomad SAS exome AF: 0.0536

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00504 AC: 7365 AN: 1461876 Hom.: 205 Cov.: 29 AF XY: 0.00632 AC XY: 4598 AN XY: 727246

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.0525

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00773

GnomAD4 genome AF: 0.0159 AC: 2422 AN: 152198 Hom.: 41 Cov.: 33 AF XY: 0.0169 AC XY: 1255 AN XY: 74418

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0658

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00352 Hom.: 8

Bravo AF: 0.0162

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Meckel syndrome, type 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.37
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7212549; hg19: chr17-19246667;