rs143978284

chr10-53807071-A-AGTT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4_Supporting PP3 BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):c.4730_4731insAAC(p.Thr1577_Gly1577insThr) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,613,496 control chromosomes in the GnomAD database, including 226 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (111 hom.)
• Consequence: PCDH15 NM_001384140.1 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.60

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001384140.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 10-53807071-A-AGTT is Benign according to our data. Variant chr10-53807071-A-AGTT is described in ClinVar as [Benign]. Clinvar id is 227002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.4730_4731insAAC	p.Thr1577_Gly1577insThr	inframe_insertion	38/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.4730_4731insAAC	p.Thr1577_Gly1577insThr	inframe_insertion	38/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3196 AN: 152122 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.0717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00551 AC: 1365 AN: 247692 Hom.: 42 AF XY: 0.00412 AC XY: 555 AN XY: 134640

Gnomad AFR exome AF: 0.0721

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000446

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00253 AC: 3700 AN: 1461256 Hom.: 111 Cov.: 32 AF XY: 0.00218 AC XY: 1585 AN XY: 726892

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.00520

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.0211 AC: 3206 AN: 152240 Hom.: 115 Cov.: 32 AF XY: 0.0203 AC XY: 1510 AN XY: 74448

Gnomad4 AFR AF: 0.0718

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00912 Hom.: 8

Bravo AF: 0.0243

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000656

EpiControl AF: 0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

p.Thr1519dup in exon 36C of PCDH15: This variant is not expected to have clinica l significance because it has been identified in 7.3% (707/9652) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs143978284). This variant is an insertion of 1 amino acid at position 1519 and is not predicted to alter the protein reading-frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143978284; hg19: chr10-55566831;