rs376844749

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2

The NM_000264.5(PTCH1):​c.3422C>T​(p.Ala1141Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1141A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 9.37
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000264.5
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.3422C>T p.Ala1141Val missense_variant 20/24 ENST00000331920.11
PTCH1NM_001083603.3 linkuse as main transcriptc.3419C>T p.Ala1140Val missense_variant 20/24 ENST00000437951.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.3422C>T p.Ala1141Val missense_variant 20/245 NM_000264.5 A2Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.3419C>T p.Ala1140Val missense_variant 20/245 NM_001083603.3 Q13635-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251306
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000328
AC:
48
AN:
1461772
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152150
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000125
Hom.:
0
Bravo
AF:
0.0000378
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Gorlin syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 14, 2024- -
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Basal cell carcinoma, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsSep 24, 2022- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 24, 2024The p.A1141V variant (also known as c.3422C>T), located in coding exon 20 of the PTCH1 gene, results from a C to T substitution at nucleotide position 3422. The alanine at codon 1141 is replaced by valine, an amino acid with similar properties. This alteration was identified in a patient suspected of having nevoid basal cell carcinoma syndrome due to her history of multiple basal cell carcinomas and two meningiomas (Brellier F et al. Br. J. Dermatol. 2008 Aug;159:445-52). This variant has been seen in an exome cohort and was classified as a variant of unknown significance by authors (Amendola LM et al. Genome Res. 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.77
D;.;.;.;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;.;D;D;.;.;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Uncertain
2.4
M;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D
REVEL
Pathogenic
0.88
Sift
Benign
0.064
T;D;D;D;D;D;T
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;D;D;.;D
Vest4
0.99
MVP
0.87
MPC
1.4
ClinPred
0.73
D
GERP RS
5.3
Varity_R
0.43
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376844749; hg19: chr9-98215787; COSMIC: COSV59469480; COSMIC: COSV59469480; API