NM_001195263.2:c.367+7A>G

Variant names:

• chr10-101023921-T-C
• rs6584410
• NM_001195263.2:c.367+7A>G

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.367+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,614,028 control chromosomes in the GnomAD database, including 287,387 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31608 hom., cov: 33)
  • Exomes 𝑓: 0.59 (255779 hom.)
• Consequence: PDZD7 NM_001195263.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002722
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.591
• Publications: 13 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 (BayesDel_noAF=-0.92).
• BP6: Variant 10-101023921-T-C is Benign according to our data. Variant chr10-101023921-T-C is described in ClinVar as Benign. ClinVar VariationId is 46211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.789 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.367+7A>G		splice_region intron	N/A	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.367+7A>G		splice_region intron	N/A	NP_001424358.1
	PDZD7	NM_001351044.2		c.367+7A>G		splice_region intron	N/A	NP_001337973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.367+7A>G		splice_region intron	N/A	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.367+7A>G		splice_region intron	N/A	ENSP00000582249.1
	PDZD7	ENST00000645349.1		c.367+7A>G		splice_region intron	N/A	ENSP00000495283.1	A0A2R8YFN1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96500 AN: 152082 Hom.: 31573 Cov.: 33

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.613

GnomAD2 exomes AF: 0.565 AC: 142062 AN: 251388 AF XY: 0.564

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.589 AC: 860722 AN: 1461828 Hom.: 255779 Cov.: 65 AF XY: 0.587 AC XY: 426665 AN XY: 727214

African (AFR) AF: 0.804 AC: 26931 AN: 33480

American (AMR) AF: 0.491 AC: 21963 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14626 AN: 26136

East Asian (EAS) AF: 0.417 AC: 16538 AN: 39700

South Asian (SAS) AF: 0.528 AC: 45556 AN: 86258

European-Finnish (FIN) AF: 0.521 AC: 27801 AN: 53390

Middle Eastern (MID) AF: 0.663 AC: 3822 AN: 5768

European-Non Finnish (NFE) AF: 0.601 AC: 667755 AN: 1111976

Other (OTH) AF: 0.592 AC: 35730 AN: 60396

GnomAD4 genome AF: 0.635 AC: 96575 AN: 152200 Hom.: 31608 Cov.: 33 AF XY: 0.626 AC XY: 46552 AN XY: 74414

African (AFR) AF: 0.796 AC: 33062 AN: 41546

American (AMR) AF: 0.569 AC: 8697 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1903 AN: 3468

East Asian (EAS) AF: 0.404 AC: 2093 AN: 5178

South Asian (SAS) AF: 0.522 AC: 2515 AN: 4820

European-Finnish (FIN) AF: 0.505 AC: 5348 AN: 10590

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40893 AN: 67986

Other (OTH) AF: 0.610 AC: 1289 AN: 2112

Alfa AF: 0.611 Hom.: 26952

Bravo AF: 0.648

Asia WGS AF: 0.486 AC: 1693 AN: 3478

EpiCase AF: 0.610

EpiControl AF: 0.612

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)
-	-	1	Hearing loss, autosomal recessive 57 (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.29
DANN	Benign	0.39
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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: rs6584410; hg19: chr10-102783678; COSMIC: COSV64645720;