rs886038205

Positions:

• chr17-19343795-C-G
• chr17-19343795-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_015681.6(B9D1):​c.467G>C​(p.Arg156Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.90

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain B9 domain-containing protein 1 (size 203) in uniprot entity B9D1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_015681.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-19343795-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 17-19343795-C-G is Pathogenic according to our data. Variant chr17-19343795-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558747.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B9D1	NM_015681.6	c.467G>C	p.Arg156Pro	missense_variant	6/7	ENST00000261499.11	NP_056496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B9D1	ENST00000261499.11	c.467G>C	p.Arg156Pro	missense_variant	6/7	1	NM_015681.6	ENSP00000261499	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Dec 04, 2014

- -

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T;.;.;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.39	T
Sift4G	Pathogenic	0.0	D;D;.;.
Vest4		0.60
MVP		0.68
ClinPred		1.0	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886038205; hg19: chr17-19247108;