rs73980038

Variant names:

• chr17-19357903-G-A
• rs73980038
• NM_015681.6:c.181C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.96
• Publications: 4 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: Genomics England PanelApp, G2P
• Joubert syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 Benign/Likely_benign. ClinVar VariationId 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	NM_015681.6	MANE Select	c.181C>T	p.Arg61Trp	missense	Exon 3 of 7	NP_056496.1
	B9D1	NM_001321214.2		c.181C>T	p.Arg61Trp	missense	Exon 3 of 7	NP_001308143.1
	B9D1	NM_001321217.2		c.181C>T	p.Arg61Trp	missense	Exon 3 of 7	NP_001308146.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.181C>T	p.Arg61Trp	missense	Exon 3 of 7	ENSP00000261499.4
	B9D1	ENST00000268841.10	TSL:1	c.181C>T	p.Arg61Trp	missense	Exon 3 of 6	ENSP00000268841.6
	B9D1	ENST00000477683.5	TSL:1	c.181C>T	p.Arg61Trp	missense	Exon 3 of 5	ENSP00000494660.1

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1492 AN: 152136 Hom.: 24 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152252 Hom.: 24 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74448

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

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Meckel syndrome, type 9 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.0
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.21
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.013	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

Other links and lift over

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