rs73980038

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_015681.6(B9D1):​c.181C>T​(p.Arg61Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,102 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0098 ( 24 hom., cov: 32)
Exomes 𝑓: 0.00099 ( 24 hom. )

Consequence

B9D1
NM_015681.6 missense

Scores

5
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.96

Publications

4 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: Genomics England PanelApp, G2P
  • Joubert syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Meckel syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6
Variant 17-19357903-G-A is Benign according to our data. Variant chr17-19357903-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260671.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 = 0.0098 (1492/152252) while in subpopulation AFR AF = 0.0341 (1418/41544). AF 95% confidence interval is 0.0327. There are 24 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
B9D1NM_015681.6 linkc.181C>T p.Arg61Trp missense_variant Exon 3 of 7 ENST00000261499.11 NP_056496.1 Q9UPM9-1B4DEW0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
B9D1ENST00000261499.11 linkc.181C>T p.Arg61Trp missense_variant Exon 3 of 7 1 NM_015681.6 ENSP00000261499.4 Q9UPM9-1

Frequencies

GnomAD3 genomes
AF:
0.00981
AC:
1492
AN:
152136
Hom.:
24
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0342
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00670
GnomAD2 exomes
AF:
0.00260
AC:
653
AN:
251442
AF XY:
0.00181
show subpopulations
Gnomad AFR exome
AF:
0.0350
Gnomad AMR exome
AF:
0.00211
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000993
AC:
1451
AN:
1461850
Hom.:
24
Cov.:
30
AF XY:
0.000846
AC XY:
615
AN XY:
727224
show subpopulations
African (AFR)
AF:
0.0360
AC:
1204
AN:
33476
American (AMR)
AF:
0.00212
AC:
95
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000151
AC:
13
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00139
AC:
8
AN:
5756
European-Non Finnish (NFE)
AF:
0.0000153
AC:
17
AN:
1111990
Other (OTH)
AF:
0.00187
AC:
113
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
83
166
249
332
415
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
38
76
114
152
190
<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:
0.00980
AC:
1492
AN:
152252
Hom.:
24
Cov.:
32
AF XY:
0.00939
AC XY:
699
AN XY:
74448
show subpopulations
African (AFR)
AF:
0.0341
AC:
1418
AN:
41544
American (AMR)
AF:
0.00346
AC:
53
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68002
Other (OTH)
AF:
0.00664
AC:
14
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
71
142
214
285
356
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
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:
0.00384
Hom.:
19
Bravo
AF:
0.0116
ESP6500AA
AF:
0.0384
AC:
169
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00309
AC:
375
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 09, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Meckel syndrome, type 9 Benign:1
Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
.;.;T;T;T;.;T;.
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.14
N
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D
MetaRNN
Benign
0.0039
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
1.8
.;.;L;.;.;L;.;.
PhyloP100
3.0
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-4.3
D;.;D;D;D;D;D;.
REVEL
Benign
0.21
Sift
Uncertain
0.012
D;.;D;D;D;D;D;.
Sift4G
Uncertain
0.013
D;.;D;D;D;D;D;.
Polyphen
0.99
.;.;D;.;.;.;.;.
Vest4
0.37
MVP
0.75
MPC
0.56
ClinPred
0.022
T
GERP RS
3.4
PromoterAI
-0.014
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.080
gMVP
0.34
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.22
Position offset: 48

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

Publications

Other links and lift over

dbSNP: rs73980038; hg19: chr17-19261216; COSMIC: COSV99265068; COSMIC: COSV99265068; API