rs200592310

Variant names:

• chr10-101019175-C-T
• rs200592310
• NM_001195263.2:c.971G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001195263.2(PDZD7):​c.971G>A​(p.Ser324Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0025 in 1,537,280 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 4.45
• Publications: 4 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008763999).
• BP6: Variant 10-101019175-C-T is Benign according to our data. Variant chr10-101019175-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164942.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00171 (261/152394) while in subpopulation NFE AF = 0.00295 (201/68040). AF 95% confidence interval is 0.00262. There are 1 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	NM_001195263.2	MANE Select	c.971G>A	p.Ser324Asn	missense	Exon 8 of 17	NP_001182192.1
	PDZD7	NM_001437429.1		c.971G>A	p.Ser324Asn	missense	Exon 8 of 17	NP_001424358.1
	PDZD7	NM_001351044.2		c.971G>A	p.Ser324Asn	missense	Exon 8 of 10	NP_001337973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.971G>A	p.Ser324Asn	missense	Exon 8 of 17	ENSP00000480489.1
	PDZD7	ENST00000645349.1		c.971G>A	p.Ser324Asn	missense	Exon 8 of 10	ENSP00000495283.1
	PDZD7	ENST00000644782.1		c.971G>A	p.Ser324Asn	missense	Exon 8 of 12	ENSP00000496747.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152276 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00181 AC: 250 AN: 137828 AF XY: 0.00202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000727

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.00259 AC: 3588 AN: 1384886 Hom.: 10 Cov.: 33 AF XY: 0.00259 AC XY: 1769 AN XY: 683508

African (AFR) AF: 0.000252 AC: 8 AN: 31756

American (AMR) AF: 0.00143 AC: 51 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 35962

South Asian (SAS) AF: 0.00278 AC: 220 AN: 79262

European-Finnish (FIN) AF: 0.00141 AC: 48 AN: 34150

Middle Eastern (MID) AF: 0.000727 AC: 4 AN: 5500

European-Non Finnish (NFE) AF: 0.00288 AC: 3107 AN: 1079424

Other (OTH) AF: 0.00252 AC: 146 AN: 57916

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152394 Hom.: 1 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74524

African (AFR) AF: 0.000361 AC: 15 AN: 41598

American (AMR) AF: 0.00124 AC: 19 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00295 AC: 201 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00173

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00177 AC: 14

ExAC AF: 0.00115 AC: 111

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	not provided (6)
-	1	-	not specified (1)
-	-	1	PDZD7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.088
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.33
MPC		0.77
ClinPred		0.068	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.49
Mutation Taster		=87/13	polymorphism

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: rs200592310; hg19: chr10-102778932;