10-27398625-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001034842.5(PTCHD3):c.1973T>C(p.Met658Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTCHD3 NM_001034842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

Genes affected

PTCHD3 (HGNC:24776): (patched domain containing 3 (gene/pseudogene)) Predicted to be located in sperm midpiece. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCHD3	NM_001034842.5	c.1973T>C	p.Met658Thr	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCHD3	ENST00000642324.1	c.1973T>C	p.Met658Thr	missense_variant	4/4			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250986 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461182 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726916

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.1973T>C (p.M658T) alteration is located in exon 4 (coding exon 4) of the PTCHD3 gene. This alteration results from a T to C substitution at nucleotide position 1973, causing the methionine (M) at amino acid position 658 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.71	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.72
MutPred		0.67		Gain of phosphorylation at M658 (P = 0.0364);
MVP		0.53
MPC		0.45
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.69

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: rs751184414; hg19: chr10-27687554;