chr10-101009290-ATCT-A

Variant names:

• chr10-101009290-ATCT-A
• rs397516636
• NM_001195263.2:c.2675_2677delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001195263.2(PDZD7):​c.2675_2677delAGA​(p.Lys892del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,535,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 7.47
• Publications: 0 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: Unknown Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

  Inheritance: AR Classification: STRONG Submitted by: 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
• PM4: Nonframeshift variant in NON repetitive region in NM_001195263.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-101009290-ATCT-A is Pathogenic according to our data. Variant chr10-101009290-ATCT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44131.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195263.2. 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
	PDZD7	NM_001195263.2	MANE Select	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 16 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.2672_2674delAGA	p.Lys891del	disruptive_inframe_deletion	Exon 16 of 17	NP_001424358.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 16 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.2672_2674delAGA	p.Lys891del	disruptive_inframe_deletion	Exon 16 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2622_*2624delAGA		non_coding_transcript_exon	Exon 12 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000365 AC: 5 AN: 136880 AF XY: 0.0000538

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000746

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 59 AN: 1383734 Hom.: 0 AF XY: 0.0000469 AC XY: 32 AN XY: 682816

African (AFR) AF: 0.0000317 AC: 1 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000528 AC: 57 AN: 1078812

Other (OTH) AF: 0.0000173 AC: 1 AN: 57906

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Hearing impairment (1)
1	-	-	Hearing loss, autosomal recessive 57 (1)
-	1	-	not specified (1)
-	1	-	PDZD7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

Other links and lift over

dbSNP: rs397516636; hg19: chr10-102769047;