rs145903555

chr10-53822169-T-Achr10-53822169-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_033056.4(PCDH15):c.5557A>T(p.Met1853Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1853T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.580

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2650833).
• BP6: Variant 10-53822169-T-A is Benign according to our data. Variant chr10-53822169-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 755082.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5557A>T	p.Met1853Leu	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-1939A>T		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5557A>T	p.Met1853Leu	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-1939A>T		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	2.4
Dann	Benign	0.47
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.10	N;.;.;N;N;N;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.053	T;.;.;T;T;T;.;T;T
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;B;B;.;B;B
Vest4		0.20
MutPred		0.72		.;.;.;Loss of ubiquitination at K1859 (P = 0.063);.;.;.;.;.;
MVP		0.41
MPC		0.027
ClinPred		0.13	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs145903555; hg19: chr10-55581929;