10-27399162-A-C

Position:

• chr10-27399162-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001034842.5(PTCHD3):​c.1436T>G​(p.Met479Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PTCHD3 NM_001034842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCHD3	NM_001034842.5	c.1436T>G	p.Met479Arg	missense_variant	4/4		NP_001030014.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCHD3	ENST00000642324.1	c.1436T>G	p.Met479Arg	missense_variant	4/4			ENSP00000495205.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459122 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 726024

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Sep 26, 2024

The c.1436T>G (p.M479R) alteration is located in exon 4 (coding exon 4) of the PTCHD3 gene. This alteration results from a T to G substitution at nucleotide position 1436, causing the methionine (M) at amino acid position 479 to be replaced by an arginine (R). 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;.
Vest4		0.80
MutPred		0.87		Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);
MVP		0.44
MPC		0.59
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-27688091;