chr17-19343350-C-A

Variant names:

• chr17-19343350-C-A
• rs758466581
• NM_015681.6:c.584G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015681.6(B9D1):​c.584G>T​(p.Gly195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,461,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.309
• Publications: 0 publications found

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]

B9D1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 27

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Meckel syndrome, type 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026764601).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000322 (47/1461868) while in subpopulation SAS AF = 0.000383 (33/86258). AF 95% confidence interval is 0.00028. There are 1 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015681.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	NM_015681.6	MANE Select	c.584G>T	p.Gly195Val	missense	Exon 7 of 7	NP_056496.1	Q9UPM9-1
	B9D1	NM_001321214.2		c.*109G>T		3_prime_UTR	Exon 7 of 7	NP_001308143.1	A8MYG7
	B9D1	NM_001321215.3		c.*360G>T		3_prime_UTR	Exon 6 of 6	NP_001308144.1	A0A2R8Y646

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.584G>T	p.Gly195Val	missense	Exon 7 of 7	ENSP00000261499.4	Q9UPM9-1
	B9D1	ENST00000642870.2		c.224G>T	p.Gly75Val	missense	Exon 7 of 7	ENSP00000496409.2	A0A2R8Y822
	B9D1	ENST00000663089.1		c.*360G>T		3_prime_UTR	Exon 7 of 7	ENSP00000499469.1	A0A590UJK9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251406 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461868 Hom.: 1 Cov.: 29 AF XY: 0.0000426 AC XY: 31 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111998

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.3
DANN	Benign	0.66
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.31
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.085
Sift	Benign	0.28	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.20		Gain of sheet (P = 0.0125)
MVP		0.16
MPC		0.26
ClinPred		0.036	T
GERP RS		-0.79
Varity_R		0.037
gMVP		0.30
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs758466581; hg19: chr17-19246663;