rs73980009

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_StrongBS1_SupportingBS2

The NM_001321218.2(B9D1):c.473-1G>C variant causes a splice acceptor, intron 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
NM_001321218.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.00006013

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:4

Conservation

PhyloP100: 0.267

Publications

2 publications found

Variant links:

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

B9D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 6.0958085 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321218.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
B9D1	NM_001321218.2	c.473-1G>C	splice_acceptor intron	N/A	NP_001308147.1
B9D1	NM_001321219.2	c.405-1G>C	splice_acceptor intron	N/A	NP_001308148.1	A0A6Q8PFJ7
B9D1	NM_001368769.2	c.113-1G>C	splice_acceptor intron	N/A	NP_001355698.1	J3QKN6

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
B9D1	ENST00000671102.1	c.536-1G>C	splice_acceptor intron	N/A	ENSP00000499690.1	A0A590UK40
B9D1	ENST00000675510.1	c.405-1G>C	splice_acceptor intron	N/A	ENSP00000501817.1	A0A6Q8PFJ7
B9D1	ENST00000674596.1	c.303-1G>C	splice_acceptor intron	N/A	ENSP00000501877.1	A0A6Q8PFN7

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1618

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00284

AC:

382

AN:

134390

AF XY:

0.00201

show subpopulations

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 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.:

Cov.:

AF XY:

0.00134

AC XY:

914

AN XY:

682074

show subpopulations

African (AFR)

AF:

0.0399

AC:

1260

AN:

31558

American (AMR)

AF:

0.00350

AC:

125

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.00139

AC:

AN:

25154

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35716

South Asian (SAS)

AF:

0.0000884

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33780

Middle Eastern (MID)

AF:

0.00812

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.000410

AC:

442

AN:

1077728

Other (OTH)

AF:

0.00379

AC:

219

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0107

AC:

1625

AN:

152298

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

748

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0355

AC:

1476

AN:

41552

American (AMR)

AF:

0.00477

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68034

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00221

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

B9D1-related disorder (1)

Joubert syndrome 27 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.8

(source)

DANN

Benign

0.52

FATHMM_MKL

Benign

0.096

PhyloP100

0.27

GERP RS

0.64

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over