9-95508258-C-T

Position:

• chr9-95508258-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4 BP6_Very_Strong BS2

The NM_000264.5(PTCH1):​c.104G>A​(p.Arg35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,440,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.07

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 -12 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=0.27005902).
• BP6: Variant 9-95508258-C-T is Benign according to our data. Variant chr9-95508258-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.104G>A	p.Arg35Gln	missense_variant	1/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1659G>A		intron_variant		ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.104G>A	p.Arg35Gln	missense_variant	1/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.199-1659G>A		intron_variant		5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000185 AC: 4 AN: 216042 Hom.: 0 AF XY: 0.0000167 AC XY: 2 AN XY: 119880

Gnomad AFR exome AF: 0.0000833

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000352

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000229 AC: 33 AN: 1440988 Hom.: 0 Cov.: 34 AF XY: 0.0000224 AC XY: 16 AN XY: 715876

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000254

Gnomad4 OTH exome AF: 0.0000505

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000255 AC: 3

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 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. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.23
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.22	B
Vest4		0.17
MutPred		0.23		Loss of methylation at R35 (P = 0.0559);
MVP		0.66
MPC		0.84
ClinPred		0.082	T
GERP RS		2.8
Varity_R		0.095
gMVP		0.44

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: rs587778627; hg19: chr9-98270540;