12-27963124-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000395868.7(PTHLH):c.*220G>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 0.0424 in 1,430,306 control chromosomes in the GnomAD database, including 1,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (199 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1493 hom.)
• Consequence: PTHLH ENST00000395868.7 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.73

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-27963124-C-T is Benign according to our data. Variant chr12-27963124-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1194658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTHLH	NM_198965.2	c.524+224G>A		intron_variant		ENST00000545234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTHLH	ENST00000545234.6	c.524+224G>A		intron_variant		5	NM_198965.2	A1
	ENST00000538113.1	n.90+4518C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6577 AN: 152098 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0977

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.0894

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0421

GnomAD4 exome AF: 0.0423 AC: 54099 AN: 1278090 Hom.: 1493 Cov.: 32 AF XY: 0.0434 AC XY: 26912 AN XY: 619798

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.0800

Gnomad4 EAS exome AF: 0.0731

Gnomad4 SAS exome AF: 0.0902

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0496

GnomAD4 genome AF: 0.0433 AC: 6595 AN: 152216 Hom.: 199 Cov.: 32 AF XY: 0.0430 AC XY: 3202 AN XY: 74428

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.0988

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.0817

Gnomad4 SAS AF: 0.0901

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0356

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0392 Hom.: 106

Bravo AF: 0.0501

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.27
Dann	Benign	0.48

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: rs6245; hg19: chr12-28116057;