NM_001195263.2:c.3092G>A

Variant names:

• chr10-101008477-C-T
• rs72838683
• NM_001195263.2:c.3092G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001195263.2(PDZD7):​c.3092G>A​(p.Arg1031His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,498,056 control chromosomes in the GnomAD database, including 2,318 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1031C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (153 hom., cov: 30)
  • Exomes 𝑓: 0.052 (2165 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01
• 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: Unknown Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017986596).
• BP6: Variant 10-101008477-C-T is Benign according to our data. Variant chr10-101008477-C-T is described in ClinVar as Benign. ClinVar VariationId is 194723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

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.3092G>A	p.Arg1031His	missense	Exon 17 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.3089G>A	p.Arg1030His	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.3092G>A	p.Arg1031His	missense	Exon 17 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.3089G>A	p.Arg1030His	missense	Exon 17 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*3039G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5410 AN: 140272 Hom.: 153 Cov.: 30

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00355

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00167

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0280

Gnomad MID AF: 0.0641

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0399

GnomAD2 exomes AF: 0.0406 AC: 4976 AN: 122554 AF XY: 0.0435

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000826

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0446

GnomAD4 exome AF: 0.0521 AC: 70756 AN: 1357696 Hom.: 2165 Cov.: 32 AF XY: 0.0524 AC XY: 34972 AN XY: 666814

African (AFR) AF: 0.00924 AC: 288 AN: 31152

American (AMR) AF: 0.0217 AC: 754 AN: 34766

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 688 AN: 23618

East Asian (EAS) AF: 0.000706 AC: 25 AN: 35420

South Asian (SAS) AF: 0.0644 AC: 4850 AN: 75320

European-Finnish (FIN) AF: 0.0266 AC: 872 AN: 32780

Middle Eastern (MID) AF: 0.0681 AC: 276 AN: 4054

European-Non Finnish (NFE) AF: 0.0566 AC: 60251 AN: 1063866

Other (OTH) AF: 0.0485 AC: 2752 AN: 56720

GnomAD4 genome AF: 0.0386 AC: 5411 AN: 140360 Hom.: 153 Cov.: 30 AF XY: 0.0379 AC XY: 2572 AN XY: 67822

African (AFR) AF: 0.0126 AC: 462 AN: 36728

American (AMR) AF: 0.0354 AC: 489 AN: 13832

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 90 AN: 3362

East Asian (EAS) AF: 0.00167 AC: 8 AN: 4788

South Asian (SAS) AF: 0.0621 AC: 273 AN: 4398

European-Finnish (FIN) AF: 0.0280 AC: 247 AN: 8832

Middle Eastern (MID) AF: 0.0590 AC: 17 AN: 288

European-Non Finnish (NFE) AF: 0.0573 AC: 3747 AN: 65342

Other (OTH) AF: 0.0385 AC: 75 AN: 1946

Alfa AF: 0.0494 Hom.: 370

Bravo AF: 0.0347

TwinsUK AF: 0.0569 AC: 211

ALSPAC AF: 0.0594 AC: 229

ExAC AF: 0.0288 AC: 853

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.070
DANN	Benign	0.75
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.0
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.24	T
Vest4		0.074
ClinPred		0.014	T
GERP RS		-9.3
Varity_R		0.017
gMVP		0.14

Splicing

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

Other links and lift over

dbSNP: rs72838683; hg19: chr10-102768234;