Variant 12-102196688-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002674.4(PMCH):c.462G>T(p.Met154Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PMCH
NM_002674.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

Genes affected

PMCH (HGNC:9109): (pro-melanin concentrating hormone) This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include melanin-concentrating hormone (MCH), neuropeptide-glutamic acid-isoleucine (NEI), and neuropeptide-glycine-glutamic acid (NGE). Melanin-concentrating hormone is a 19-amino acid neuropeptide that stimulates hunger and may additionally regulate energy homeostasis, reproductive function, and sleep. Pseudogenes of this gene have been identified on chromosome 5. [provided by RefSeq, Jul 2015]

PMCH links:

PARPBP (HGNC:26074): (PARP1 binding protein) Predicted to enable DNA binding activity. Involved in negative regulation of double-strand break repair via homologous recombination. Located in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PARPBP links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMCH	NM_002674.4 linkuse as main transcript	c.462G>T	p.Met154Ile	missense_variant	3/3	ENST00000329406.5
PARPBP	NM_017915.5 linkuse as main transcript	c.*397C>A		3_prime_UTR_variant	11/11	ENST00000327680.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMCH	ENST00000329406.5 linkuse as main transcript	c.462G>T	p.Met154Ile	missense_variant	3/3	1	NM_002674.4	P1
PARPBP	ENST00000327680.7 linkuse as main transcript	c.*397C>A		3_prime_UTR_variant	11/11	2	NM_017915.5	P1	Q9NWS1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457116

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.462G>T (p.M154I) alteration is located in exon 3 (coding exon 3) of the PMCH gene. This alteration results from a G to T substitution at nucleotide position 462, causing the methionine (M) at amino acid position 154 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

0.95

Vest4

0.79

MutPred

0.75

Loss of MoRF binding (P = 0.0954);

MVP

0.74

MPC

0.16

ClinPred

0.97

GERP RS

4.9

Varity_R

0.60

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over