rs34616847

Variant names:

• chr10-101010757-T-C
• rs34616847
• NM_001195263.2:c.2132A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-101010757-T-C
• chr10-101010757-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195263.2(PDZD7):​c.2132A>G​(p.His711Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,319,644 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 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. H711L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (82 hom., cov: 30)
  • Exomes 𝑓: 0.033 (638 hom.)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.42
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002282381).
• BP6: Variant 10-101010757-T-C is Benign according to our data. Variant chr10-101010757-T-C is described in ClinVar as Benign. ClinVar VariationId is 44122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0295 (4119/139684) while in subpopulation AFR AF = 0.0357 (1342/37610). AF 95% confidence interval is 0.0341. There are 82 homozygotes in GnomAd4. There are 1978 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 Unknown,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	NM_001195263.2	MANE Select	c.2132A>G	p.His711Arg	missense	Exon 15 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.2129A>G	p.His710Arg	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.2132A>G	p.His711Arg	missense	Exon 15 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.2129A>G	p.His710Arg	missense	Exon 15 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2079A>G		non_coding_transcript_exon	Exon 11 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4110 AN: 139592 Hom.: 81 Cov.: 30

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000223

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0369

GnomAD2 exomes AF: 0.0256 AC: 3330 AN: 130090 AF XY: 0.0259

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.0000958

Gnomad FIN exome AF: 0.0504

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0334 AC: 39455 AN: 1179960 Hom.: 638 Cov.: 45 AF XY: 0.0333 AC XY: 19370 AN XY: 581500

African (AFR) AF: 0.0432 AC: 1170 AN: 27090

American (AMR) AF: 0.0191 AC: 586 AN: 30608

Ashkenazi Jewish (ASJ) AF: 0.0685 AC: 1294 AN: 18900

East Asian (EAS) AF: 0.000173 AC: 3 AN: 17342

South Asian (SAS) AF: 0.0275 AC: 2118 AN: 76890

European-Finnish (FIN) AF: 0.0877 AC: 1572 AN: 17926

Middle Eastern (MID) AF: 0.0312 AC: 146 AN: 4682

European-Non Finnish (NFE) AF: 0.0329 AC: 30976 AN: 940870

Other (OTH) AF: 0.0348 AC: 1590 AN: 45652

GnomAD4 genome AF: 0.0295 AC: 4119 AN: 139684 Hom.: 82 Cov.: 30 AF XY: 0.0292 AC XY: 1978 AN XY: 67834

African (AFR) AF: 0.0357 AC: 1342 AN: 37610

American (AMR) AF: 0.0195 AC: 277 AN: 14172

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 199 AN: 3300

East Asian (EAS) AF: 0.000223 AC: 1 AN: 4480

South Asian (SAS) AF: 0.0253 AC: 104 AN: 4110

European-Finnish (FIN) AF: 0.0486 AC: 428 AN: 8812

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0262 AC: 1679 AN: 64100

Other (OTH) AF: 0.0365 AC: 72 AN: 1974

Alfa AF: 0.0272 Hom.: 13

Bravo AF: 0.0266

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0278 AC: 107

ExAC AF: 0.0184 AC: 400

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.79
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.37	T
Vest4		0.057
ClinPred		0.054	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.21

Splicing

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

Other links and lift over

dbSNP: rs34616847; hg19: chr10-102770514; COSMIC: COSV64651828; COSMIC: COSV64651828;