rs111033496

Variant names:

• chr10-53857186-T-A
• rs111033496
• NM_033056.4:c.3795A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-53857186-T-A
• chr10-53857186-T-C
• chr10-53857186-T-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001384140.1(PCDH15):​c.3795A>T​(p.Glu1265Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,597,542 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (62 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (52 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0190
• Publications: 4 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, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -16 ACMG points.

• BP6: Variant 10-53857186-T-A is Benign according to our data. Variant chr10-53857186-T-A is described in ClinVar as Benign. ClinVar VariationId is 46474.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 = 0.0142 (2153/152150) while in subpopulation AFR AF = 0.0491 (2039/41504). AF 95% confidence interval is 0.0474. There are 62 homozygotes in GnomAd4. There are 1051 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

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_033056.4	MANE Plus Clinical	c.3795A>T	p.Glu1265Asp	missense	Exon 28 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3795A>T	p.Glu1265Asp	missense	Exon 28 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.3810A>T	p.Glu1270Asp	missense	Exon 29 of 35	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3795A>T	p.Glu1265Asp	missense	Exon 28 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3795A>T	p.Glu1265Asp	missense	Exon 28 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3816A>T	p.Glu1272Asp	missense	Exon 29 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2138 AN: 152034 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00367 AC: 921 AN: 250960 AF XY: 0.00274

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00141 AC: 2037 AN: 1445392 Hom.: 52 Cov.: 29 AF XY: 0.00120 AC XY: 864 AN XY: 719950

African (AFR) AF: 0.0500 AC: 1651 AN: 33016

American (AMR) AF: 0.00251 AC: 112 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00507 AC: 29 AN: 5718

European-Non Finnish (NFE) AF: 0.0000474 AC: 52 AN: 1097544

Other (OTH) AF: 0.00296 AC: 177 AN: 59820

GnomAD4 genome AF: 0.0142 AC: 2153 AN: 152150 Hom.: 62 Cov.: 31 AF XY: 0.0141 AC XY: 1051 AN XY: 74390

African (AFR) AF: 0.0491 AC: 2039 AN: 41504

American (AMR) AF: 0.00505 AC: 77 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67996

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00260 Hom.: 4

Bravo AF: 0.0161

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00434 AC: 15 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.019
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.14
Sift	Benign	0.32	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.48		Gain of sheet (P = 0.039)
MVP		0.60
MPC		0.027
ClinPred		0.0082	T
GERP RS		5.2
PromoterAI		-0.0080	Neutral
Varity_R		0.088
gMVP		0.39
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.40		Position offset: -11

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

Other links and lift over

dbSNP: rs111033496; hg19: chr10-55616946;