17-19347840-G-T

Variant names:

• chr17-19347840-G-T
• rs373478202
• NM_015681.6:c.285C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015681.6(B9D1):​c.285C>A​(p.Phe95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F95F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.0960
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 17-19347840-G-T is Pathogenic according to our data. Variant chr17-19347840-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217553.

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.285C>A	p.Phe95Leu	missense	Exon 4 of 7	NP_056496.1	Q9UPM9-1
	B9D1	NM_001321214.2		c.285C>A	p.Phe95Leu	missense	Exon 4 of 7	NP_001308143.1	A8MYG7
	B9D1	NM_001321217.2		c.285C>A	p.Phe95Leu	missense	Exon 4 of 7	NP_001308146.1	A0A0B4J223

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.285C>A	p.Phe95Leu	missense	Exon 4 of 7	ENSP00000261499.4	Q9UPM9-1
	B9D1	ENST00000268841.10	TSL:1	c.285C>A	p.Phe95Leu	missense	Exon 4 of 6	ENSP00000268841.6	Q9UPM9-2
	B9D1	ENST00000477683.5	TSL:1	c.285C>A	p.Phe95Leu	missense	Exon 4 of 5	ENSP00000494660.1	A0A2R8Y5M4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251140 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000205 AC: 3 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

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

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	7.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.096
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.25
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.11	B
Vest4		0.84
MutPred		0.84		Loss of sheet (P = 0.1158)
MVP		0.62
MPC		0.28
ClinPred		0.73	D
GERP RS		-3.9
Varity_R		0.52
gMVP		0.30
Mutation Taster		=13/187	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 40

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

Other links and lift over

dbSNP: rs373478202; hg19: chr17-19251153; COSMIC: COSV52069595; COSMIC: COSV52069595;