chr10-53903374-G-A

Variant names:

• chr10-53903374-G-A
• rs111739360
• NM_033056.4:c.3374-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.3374-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,170 control chromosomes in the GnomAD database, including 193 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 0.020 (98 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (95 hom.)
• Consequence: PCDH15 NM_033056.4 splice_region, intron
• Scores: Splicing: ADA: 0.0008929
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.563
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-53903374-G-A is Benign according to our data. Variant chr10-53903374-G-A is described in ClinVar as Benign. ClinVar VariationId is 46466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.3374-4C>T		splice_region intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3374-4C>T		splice_region intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.3389-4C>T		splice_region intron	N/A	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3374-4C>T		splice_region intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3374-4C>T		splice_region intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3395-4C>T		splice_region intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3000 AN: 152010 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.00610 AC: 1529 AN: 250460 AF XY: 0.00460

Gnomad AFR exome AF: 0.0712

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000943

Gnomad NFE exome AF: 0.000890

Gnomad OTH exome AF: 0.00476

GnomAD4 exome AF: 0.00256 AC: 3745 AN: 1460042 Hom.: 95 Cov.: 31 AF XY: 0.00235 AC XY: 1707 AN XY: 726366

African (AFR) AF: 0.0688 AC: 2300 AN: 33440

American (AMR) AF: 0.00657 AC: 294 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00284 AC: 74 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86224

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52684

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5758

European-Non Finnish (NFE) AF: 0.000578 AC: 642 AN: 1111192

Other (OTH) AF: 0.00567 AC: 342 AN: 60344

GnomAD4 genome AF: 0.0199 AC: 3020 AN: 152128 Hom.: 98 Cov.: 32 AF XY: 0.0198 AC XY: 1470 AN XY: 74380

African (AFR) AF: 0.0655 AC: 2719 AN: 41504

American (AMR) AF: 0.0134 AC: 205 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67956

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.0113 Hom.: 41

Bravo AF: 0.0229

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.1
DANN	Benign	0.84
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00089
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs111739360; hg19: chr10-55663134;