chr10-53807071-A-AGTT

Variant names:

• chr10-53807071-A-AGTT
• rs143978284
• NM_001384140.1:c.4728_4730dupAAC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4_Supporting PP3 BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.4728_4730dupAAC​(p.Thr1577dup) variant causes a disruptive 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 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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
	PCDH15	NM_001384140.1	MANE Select	c.4728_4730dupAAC	p.Thr1577dup	disruptive_inframe_insertion	Exon 38 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001354429.2		c.4662_4664dupAAC	p.Thr1555dup	disruptive_inframe_insertion	Exon 37 of 37	NP_001341358.1
	PCDH15	NM_001142771.2		c.4554_4556dupAAC	p.Thr1519dup	disruptive_inframe_insertion	Exon 36 of 36	NP_001136243.1	A0A087X1T6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.4728_4730dupAAC	p.Thr1577dup	disruptive_inframe_insertion	Exon 38 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4533_4535dupAAC	p.Thr1512dup	disruptive_inframe_insertion	Exon 34 of 34	ENSP00000483745.1	Q96QU1-6
	PCDH15	ENST00000621708.4	TSL:5	c.4554_4556dupAAC	p.Thr1519dup	disruptive_inframe_insertion	Exon 36 of 36	ENSP00000484454.1	A0A087X1T6

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

GnomAD2 exomes AF: 0.00551 AC: 1365 AN: 247692 AF XY: 0.00412

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 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

African (AFR) AF: 0.0759 AC: 2540 AN: 33458

American (AMR) AF: 0.00520 AC: 232 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5758

European-Non Finnish (NFE) AF: 0.000435 AC: 484 AN: 1111702

Other (OTH) AF: 0.00580 AC: 350 AN: 60358

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

African (AFR) AF: 0.0718 AC: 2980 AN: 41530

American (AMR) AF: 0.00974 AC: 149 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68016

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=67/33	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs143978284; hg19: chr10-55566831;