rs143414291

Variant names:

• chr10-101010745-G-A
• rs143414291
• NM_001195263.2:c.2144C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001195263.2(PDZD7):​c.2144C>T​(p.Pro715Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P715S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 29)
  • Exomes 𝑓: 0.011 (80 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.25
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062847733).
• BP6: Variant 10-101010745-G-A is Benign according to our data. Variant chr10-101010745-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2144C>T	p.Pro715Leu	missense	Exon 15 of 17	NP_001182192.1
	PDZD7	NM_001437429.1		c.2141C>T	p.Pro714Leu	missense	Exon 15 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.2144C>T	p.Pro715Leu	missense	Exon 15 of 17	ENSP00000480489.1
	PDZD7	ENST00000912190.1		c.2141C>T	p.Pro714Leu	missense	Exon 15 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2091C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000474447.1

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1168 AN: 145922 Hom.: 10 Cov.: 29

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00454

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00321

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0123

GnomAD2 exomes AF: 0.00750 AC: 974 AN: 129826 AF XY: 0.00717

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0000959

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00769

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0110 AC: 12944 AN: 1181656 Hom.: 80 Cov.: 43 AF XY: 0.0108 AC XY: 6291 AN XY: 584122

African (AFR) AF: 0.00168 AC: 45 AN: 26822

American (AMR) AF: 0.00775 AC: 242 AN: 31230

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 359 AN: 18998

East Asian (EAS) AF: 0.0000488 AC: 1 AN: 20484

South Asian (SAS) AF: 0.00303 AC: 232 AN: 76664

European-Finnish (FIN) AF: 0.0222 AC: 436 AN: 19606

Middle Eastern (MID) AF: 0.0113 AC: 55 AN: 4856

European-Non Finnish (NFE) AF: 0.0118 AC: 11024 AN: 936860

Other (OTH) AF: 0.0119 AC: 550 AN: 46136

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00800 AC: 1168 AN: 146054 Hom.: 10 Cov.: 29 AF XY: 0.00803 AC XY: 571 AN XY: 71112

African (AFR) AF: 0.00190 AC: 76 AN: 40008

American (AMR) AF: 0.0123 AC: 179 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 54 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4712

South Asian (SAS) AF: 0.00298 AC: 13 AN: 4360

European-Finnish (FIN) AF: 0.0118 AC: 113 AN: 9568

Middle Eastern (MID) AF: 0.0140 AC: 4 AN: 286

European-Non Finnish (NFE) AF: 0.0106 AC: 700 AN: 66192

Other (OTH) AF: 0.0122 AC: 25 AN: 2050

Alfa AF: 0.0101 Hom.: 5

Bravo AF: 0.00798

ExAC AF: 0.00492 AC: 108

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.79
Eigen	Benign	-0.042
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.99	T
PhyloP100		3.2
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.021	D
Vest4		0.17
MVP		0.093
ClinPred		0.094	T
GERP RS		3.5
Varity_R		0.066
gMVP		0.37

Splicing

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

Other links and lift over

dbSNP: rs143414291; hg19: chr10-102770502; COSMIC: COSV64652378; COSMIC: COSV64652378;