19-45145823-T-G

Variant names:

• chr19-45145823-T-G
• rs765288398
• NM_019121.2:c.1767T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_019121.2(PPP1R37):​c.1767T>G​(p.Pro589Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P589P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: PPP1R37 NM_019121.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.902
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP7: Synonymous conserved (PhyloP=-0.902 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R37	NM_019121.2	c.1767T>G	p.Pro589Pro	synonymous_variant	Exon 11 of 13	ENST00000221462.9	NP_061994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R37	ENST00000221462.9	c.1767T>G	p.Pro589Pro	synonymous_variant	Exon 11 of 13	5	NM_019121.2	ENSP00000221462.3
PPP1R37	ENST00000422370.2	n.3689T>G		non_coding_transcript_exon_variant	Exon 3 of 3	1
PPP1R37	ENST00000540059.1	n.692T>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
MARK4	ENST00000587566.5	c.-277+66446T>G		intron_variant	Intron 1 of 6	5		ENSP00000465414.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000463 AC: 1 AN: 215924 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 109916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4512

American (AMR) AF: 0.00 AC: 0 AN: 5810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5352

South Asian (SAS) AF: 0.00 AC: 0 AN: 22514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 622

European-Non Finnish (NFE) AF: 0.00000629 AC: 1 AN: 158902

Other (OTH) AF: 0.00 AC: 0 AN: 9352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.083
DANN	Benign	0.33
PhyloP100		-0.90

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: rs765288398; hg19: chr19-45649081;