12-27963178-C-T

Variant names:

• chr12-27963178-C-T
• rs2796
• ENST00000395868.7:c.*166G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002820.3(PTHLH):​c.*166G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,499,164 control chromosomes in the GnomAD database, including 2,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (228 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1897 hom.)
• Consequence: PTHLH NM_002820.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.96
• Publications: 12 publications found

Genes affected

PTHLH (HGNC:9607): (parathyroid hormone like hormone) The protein encoded by this gene is a member of the parathyroid hormone family. This hormone, via its receptor, PTHR1, regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. It is responsible for most cases of humoral hypercalcemia of malignancy, and mutations in this gene are associated with brachydactyly type E2 (BDE2). Alternatively spliced transcript variants have been found for this gene. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, downstream of the initiator AUG codon, resulting in nuclear forms of this hormone. [provided by RefSeq, Nov 2013]

PTHLH Gene-Disease associations (from GenCC):

• brachydactyly type E2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• brachydactyly type E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000257042 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-27963178-C-T is Benign according to our data. Variant chr12-27963178-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1193892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002820.3. 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
	PTHLH	NM_198965.2	MANE Select	c.524+170G>A		intron	N/A	NP_945316.1	P12272-1
	PTHLH	NM_002820.3		c.*166G>A		3_prime_UTR	Exon 4 of 4	NP_002811.1	P12272-2
	PTHLH	NM_198964.2		c.*166G>A		3_prime_UTR	Exon 3 of 3	NP_945315.1	P12272-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTHLH	ENST00000395868.7	TSL:1	c.*166G>A		3_prime_UTR	Exon 3 of 3	ENSP00000379209.3	P12272-2
	PTHLH	ENST00000535992.5	TSL:1	c.*166G>A		3_prime_UTR	Exon 3 of 3	ENSP00000440613.1	P12272-2
	PTHLH	ENST00000545234.6	TSL:5 MANE Select	c.524+170G>A		intron	N/A	ENSP00000441765.1	P12272-1

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6810 AN: 152090 Hom.: 226 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0447 AC: 60274 AN: 1346956 Hom.: 1897 Cov.: 32 AF XY: 0.0456 AC XY: 30061 AN XY: 659728

African (AFR) AF: 0.0242 AC: 749 AN: 30904

American (AMR) AF: 0.157 AC: 5223 AN: 33340

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 1666 AN: 22684

East Asian (EAS) AF: 0.115 AC: 4053 AN: 35376

South Asian (SAS) AF: 0.0887 AC: 6326 AN: 71296

European-Finnish (FIN) AF: 0.0220 AC: 738 AN: 33480

Middle Eastern (MID) AF: 0.0467 AC: 181 AN: 3878

European-Non Finnish (NFE) AF: 0.0363 AC: 38422 AN: 1059776

Other (OTH) AF: 0.0519 AC: 2916 AN: 56222

GnomAD4 genome AF: 0.0449 AC: 6828 AN: 152208 Hom.: 228 Cov.: 32 AF XY: 0.0446 AC XY: 3321 AN XY: 74396

African (AFR) AF: 0.0263 AC: 1093 AN: 41524

American (AMR) AF: 0.0994 AC: 1519 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3468

East Asian (EAS) AF: 0.134 AC: 695 AN: 5170

South Asian (SAS) AF: 0.0906 AC: 437 AN: 4822

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10602

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0351 AC: 2388 AN: 68016

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0404 Hom.: 260

Bravo AF: 0.0519

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.80
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2796; hg19: chr12-28116111;