rs202111971

Positions:

• chr9-95516690-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083603.3(PTCH1):​c.131A>G​(p.Glu44Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,612,088 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: PTCH1 NM_001083603.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.81

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002708137).
• BP6: Variant 9-95516690-T-C is Benign according to our data. Variant chr9-95516690-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 41768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95516690-T-C is described in Lovd as [Likely_benign]. Variant chr9-95516690-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00684 (1037/151610) while in subpopulation AFR AF= 0.0218 (899/41310). AF 95% confidence interval is 0.0206. There are 13 homozygotes in gnomad4. There are 521 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1037 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_001083603.3	c.131A>G	p.Glu44Gly	missense_variant	1/24	ENST00000437951.6	NP_001077072.1
PTCH1	NM_001083602.3	c.-219A>G		5_prime_UTR_variant	1/24		NP_001077071.1
PTCH1	NM_001354919.2	c.-219A>G		5_prime_UTR_variant	1/5		NP_001341848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000437951.6	c.131A>G	p.Glu44Gly	missense_variant	1/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1039 AN: 151490 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00625

GnomAD3 exomes AF: 0.00281 AC: 694 AN: 246616 Hom.: 9 AF XY: 0.00254 AC XY: 341 AN XY: 134070

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1460478 Hom.: 17 Cov.: 31 AF XY: 0.000932 AC XY: 677 AN XY: 726592

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00921

Gnomad4 SAS exome AF: 0.000465

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00684 AC: 1037 AN: 151610 Hom.: 13 Cov.: 32 AF XY: 0.00703 AC XY: 521 AN XY: 74108

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00666

Alfa AF: 0.00224 Hom.: 5

Bravo AF: 0.00773

ESP6500AA AF: 0.0154 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00305 AC: 369

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	This variant is associated with the following publications: (PMID: 24728327) -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTCH1 p.Glu44Gly variant was identified in dbSNP (ID: rs202111971) and in ClinVar (classified as benign by the Biesecker Lab/Human Development Section, National Institutes of Health) but was not identified in Cosmic or LOVD 3.0. The variant was also identified in control databases in 921 of 277682 chromosomes (13 homozygous) at a frequency of 0.003317 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 526 of 23938 chromosomes (freq: 0.02197), East Asian in 296 of 19242 chromosomes (freq: 0.01538), Other in 17 of 7066 chromosomes (freq: 0.002406), Latino in 55 of 34712 chromosomes (freq: 0.001584), South Asian in 13 of 30206 chromosomes (freq: 0.00043) and European (non-Finnish) in 14 of 127278 chromosomes (freq: 0.00011), while the variant was not observed in the Ashkenazi Jewish and European (Finnish) populations. The variant was identified in 2/177 healthy controls in a study that identified variants in cancer genes in participants without a personal or family history of cancer (Johnston_2012_PMID:22703879). The p.Glu44G residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

PTCH1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.4
DANN	Benign	0.93
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.76	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.22
Sift	Benign	0.81	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.39
ClinPred		0.00089	T
GERP RS		-1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202111971; hg19: chr9-98278972; COSMIC: COSV64594740; COSMIC: COSV64594740;