chr19-45140521-A-G

Position:

• chr19-45140521-A-G

Variant summary

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

The NM_019121.2(PPP1R37):​c.362A>G​(p.Tyr121Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000202 in 1,383,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PPP1R37 NM_019121.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

Genes affected

PPP1R37 (HGNC:27607): (protein phosphatase 1 regulatory subunit 37) Predicted to enable protein phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

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
PPP1R37	NM_019121.2	c.362A>G	p.Tyr121Cys	missense_variant	4/13	ENST00000221462.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R37	ENST00000221462.9	c.362A>G	p.Tyr121Cys	missense_variant	4/13	5	NM_019121.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000202 AC: 28 AN: 1383624 Hom.: 0 Cov.: 31 AF XY: 0.0000161 AC XY: 11 AN XY: 682762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 30, 2023

The c.362A>G (p.Y121C) alteration is located in exon 4 (coding exon 4) of the PPP1R37 gene. This alteration results from a A to G substitution at nucleotide position 362, causing the tyrosine (Y) at amino acid position 121 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.97
DEOGEN2	Benign	0.074	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.28
Sift	Benign	0.093	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.98	D;.
Vest4		0.67
MutPred		0.40		Gain of methylation at K122 (P = 0.0238);.;
MVP		0.37
ClinPred		0.94	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.57

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: rs911870919; hg19: chr19-45643779;