12-27963425-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Strong BP6_Moderate BS2

The NM_198965.2(PTHLH):c.447C>G(p.Asp149Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PTHLH NM_198965.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.516

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 -8 ACMG points.

• PM1: In a chain Parathyroid hormone-related protein (size 140) in uniprot entity PTHR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_198965.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036930442).
• BP6: Variant 12-27963425-G-C is Benign according to our data. Variant chr12-27963425-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 717354.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTHLH	NM_198965.2	c.447C>G	p.Asp149Glu	missense_variant	5/6	ENST00000545234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTHLH	ENST00000545234.6	c.447C>G	p.Asp149Glu	missense_variant	5/6	5	NM_198965.2	A1
	ENST00000538113.1	n.90+4819G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000334 AC: 84 AN: 251462 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00440

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.000116 AC XY: 84 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00395

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000301 Hom.: 1

Bravo AF: 0.000268

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Invitae

Jul 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	8.3
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T;T;.;.;.;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.75	T;.;.;T;T;.;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N;N;N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.17	N;N;N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.28	T;T;T;T;T;T;T;T
Sift4G	Benign	0.91	T;T;T;T;T;T;T;T
Polyphen		0.0050	B;B;B;.;.;.;.;.
Vest4		0.078
MutPred		0.20		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.20
MPC		0.62
ClinPred		0.0090	T
GERP RS		3.5
Varity_R		0.050
gMVP		0.044

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: rs199690911; hg19: chr12-28116358;