12-102197051-C-T

Position:

• chr12-102197051-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002674.4(PMCH):​c.370G>A​(p.Glu124Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMCH NM_002674.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMCH	NM_002674.4	c.370G>A	p.Glu124Lys	missense_variant	2/3	ENST00000329406.5
PARPBP	NM_017915.5	c.*760C>T		3_prime_UTR_variant	11/11	ENST00000327680.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMCH	ENST00000329406.5	c.370G>A	p.Glu124Lys	missense_variant	2/3	1	NM_002674.4	P1
PARPBP	ENST00000327680.7	c.*760C>T		3_prime_UTR_variant	11/11	2	NM_017915.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

The c.370G>A (p.E124K) alteration is located in exon 2 (coding exon 2) of the PMCH gene. This alteration results from a G to A substitution at nucleotide position 370, causing the glutamic acid (E) at amino acid position 124 to be replaced by a lysine (K). 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	Benign	0.15
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.65		Gain of ubiquitination at E124 (P = 0.0025);
MVP		0.79
MPC		0.23
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.23
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-102590829;