10-101008478-G-A

Variant names:

• chr10-101008478-G-A
• rs772704936
• NM_001195263.2:c.3091C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001195263.2(PDZD7):​c.3091C>T​(p.Arg1031Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,517,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1031H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.830
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066346794).

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.3091C>T	p.Arg1031Cys	missense	Exon 17 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.3088C>T	p.Arg1030Cys	missense	Exon 17 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.3091C>T	p.Arg1031Cys	missense	Exon 17 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.3088C>T	p.Arg1030Cys	missense	Exon 17 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*3038C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151860 Hom.: 0 Cov.: 30

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000400 AC: 5 AN: 125106 AF XY: 0.0000599

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000417

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: 0.0000212 AC: 29 AN: 1365690 Hom.: 0 Cov.: 32 AF XY: 0.0000238 AC XY: 16 AN XY: 671274

African (AFR) AF: 0.00 AC: 0 AN: 31306

American (AMR) AF: 0.0000285 AC: 1 AN: 35050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23942

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35546

South Asian (SAS) AF: 0.000131 AC: 10 AN: 76168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33636

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4108

European-Non Finnish (NFE) AF: 0.0000150 AC: 16 AN: 1068850

Other (OTH) AF: 0.00 AC: 0 AN: 57084

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151978 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000335 AC: 1

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.9
DANN	Benign	0.73
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.83
PrimateAI	Benign	0.23	T
Sift4G	Uncertain	0.0040	D
Vest4		0.12
MVP		0.043
ClinPred		0.23	T
GERP RS		1.6
Varity_R		0.086
gMVP		0.26

Splicing

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

Other links and lift over

dbSNP: rs772704936; hg19: chr10-102768235;