rs142148876

Variant names:

• chr9-95447128-G-A
• rs142148876
• NM_000264.5:c.4128C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95447128-G-A
• chr9-95447128-G-T
• chr9-95447128-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):​c.4128C>T​(p.Ser1376Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,613,274 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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. S1376S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (7 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.38
• Publications: 2 publications found

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]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 9-95447128-G-A is Benign according to our data. Variant chr9-95447128-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000689 (105/152346) while in subpopulation SAS AF = 0.00641 (31/4834). AF 95% confidence interval is 0.00464. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 105 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.4128C>T	p.Ser1376Ser	synonymous	Exon 23 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.4125C>T	p.Ser1375Ser	synonymous	Exon 23 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3972C>T	p.Ser1324Ser	synonymous	Exon 22 of 23	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.4128C>T	p.Ser1376Ser	synonymous	Exon 23 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.4125C>T	p.Ser1375Ser	synonymous	Exon 23 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3675C>T	p.Ser1225Ser	synonymous	Exon 23 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00142 AC: 352 AN: 247144 AF XY: 0.00166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.000926

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000970 AC: 1417 AN: 1460928 Hom.: 7 Cov.: 30 AF XY: 0.00114 AC XY: 828 AN XY: 726794

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000403 AC: 18 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26114

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39696

South Asian (SAS) AF: 0.00548 AC: 473 AN: 86246

European-Finnish (FIN) AF: 0.000570 AC: 30 AN: 52664

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.000687 AC: 764 AN: 1111888

Other (OTH) AF: 0.00108 AC: 65 AN: 60368

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74506

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5174

South Asian (SAS) AF: 0.00641 AC: 31 AN: 4834

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000730 Hom.: 0

Bravo AF: 0.000601

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Gorlin syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Holoprosencephaly 7 (1)
-	-	1	Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.8
DANN	Benign	0.77
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs142148876; hg19: chr9-98209410;