chr19-45093360-C-A

Variant names:

• chr19-45093360-C-A
• rs1368890891
• NM_019121.2:c.35C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019121.2(PPP1R37):​c.35C>A​(p.Pro12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PPP1R37 NM_019121.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

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]

MARK4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27458325).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019121.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R37	NM_019121.2	MANE Select	c.35C>A	p.Pro12Gln	missense	Exon 1 of 13	NP_061994.1	O75864-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R37	ENST00000221462.9	TSL:5 MANE Select	c.35C>A	p.Pro12Gln	missense	Exon 1 of 13	ENSP00000221462.3	O75864-1
	PPP1R37	ENST00000945762.1		c.35C>A	p.Pro12Gln	missense	Exon 1 of 14	ENSP00000615821.1
	PPP1R37	ENST00000872789.1		c.35C>A	p.Pro12Gln	missense	Exon 1 of 13	ENSP00000542848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355692 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 666484

African (AFR) AF: 0.00 AC: 0 AN: 28860

American (AMR) AF: 0.00 AC: 0 AN: 33332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24412

East Asian (EAS) AF: 0.00 AC: 0 AN: 33604

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063466

Other (OTH) AF: 0.00 AC: 0 AN: 56452

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	T
Eigen	Benign	0.068
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.089
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.93	P
Vest4		0.15
MutPred		0.12		Loss of catalytic residue at P12 (P = 0.1111)
MVP		0.31
ClinPred		0.65	D
GERP RS		3.0
PromoterAI		-0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.29
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1368890891; hg19: chr19-45596618;