rs1554835827

Variant names:

• chr10-101021811-A-C
• rs1554835827
• NM_001195263.2:c.854T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001195263.2(PDZD7):​c.854T>G​(p.Met285Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M285V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.59
• Publications: 2 publications found

Genes affected

PDZD7 (HGNC:26257): (PDZ domain containing 7) This gene encodes a ciliary protein homologous to proteins which are mutated in Usher syndrome patients, and mutations and translocations involving this gene have been associated with two types of Usher syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

PDZD7 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 2C

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-101021811-A-C is Pathogenic according to our data. Variant chr10-101021811-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545400.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.854T>G	p.Met285Arg	missense_variant	Exon 6 of 17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.854T>G	p.Met285Arg	missense_variant	Exon 6 of 17	5	NM_001195263.2	ENSP00000480489.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, autosomal recessive 57 Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Deafness, autosomal recessive, 57. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://www.uniprot.org/uniprot/Q9H5P4) (https://prosite.expasy.org/PDOC50106). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/26416264). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/26416264). -

Jun 01, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.81	N;N;.;N;.
PhyloP100		8.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	.;.;.;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.032	.;.;.;D;.
Sift4G	Uncertain	0.0020	.;D;.;D;.
Polyphen		0.93	P;P;.;.;.
Vest4		0.96, 0.97
MutPred		0.57		Gain of MoRF binding (P = 0.0306);Gain of MoRF binding (P = 0.0306);Gain of MoRF binding (P = 0.0306);Gain of MoRF binding (P = 0.0306);Gain of MoRF binding (P = 0.0306);
MVP		0.70
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.90
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554835827; hg19: chr10-102781568;