rs757579309

Positions:

• chr9-95479978-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Moderate BP6_Very_Strong BS2

The NM_000264.5(PTCH1):​c.1058A>G​(p.Lys353Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,894 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K353K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.60

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21781784).
• BP6: Variant 9-95479978-T-C is Benign according to our data. Variant chr9-95479978-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 453768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1058A>G	p.Lys353Arg	missense_variant	7/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1055A>G	p.Lys352Arg	missense_variant	7/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1058A>G	p.Lys353Arg	missense_variant	7/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1055A>G	p.Lys352Arg	missense_variant	7/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251496 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

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: 0.0000178 AC: 26 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T;.;.;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.027	D
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.
MutationTaster	Benign	0.74	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.070	N;N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.39	T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;.
Polyphen		0.010	B;B;B;B;B;B;B;.
Vest4		0.28
MutPred		0.42		Loss of ubiquitination at K353 (P = 0.0233);.;.;.;.;.;.;.;
MVP		0.51
MPC		0.44
ClinPred		0.089	T
GERP RS		6.0
Varity_R		0.19
gMVP		0.24

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: rs757579309; hg19: chr9-98242260;