2-31883450-C-T

Variant names:

• chr2-31883450-C-T
• rs764340840
• NM_001301833.4:c.593G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001301833.4(MEMO1):​c.593G>A​(p.Arg198His) variant causes a missense change. The variant allele was found at a frequency of 0.0000063 in 1,587,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MEMO1 NM_001301833.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 1 publications found

Genes affected

MEMO1 (HGNC:14014): (mediator of cell motility 1) Involved in regulation of microtubule-based process. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DPY30 (HGNC:24590): (dpy-30 histone methyltransferase complex regulatory subunit) This gene encodes an integral core subunit of the SET1/MLL family of H3K4 methyltransferases. The encoded protein directly controls cell cycle regulators and plays an important role in the proliferation and differentiation of human hematopoietic progenitor cells. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21318814).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301833.4. 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
	MEMO1	NM_001301833.4	MANE Select	c.593G>A	p.Arg198His	missense	Exon 8 of 10	NP_001288762.1	Q9Y316-1
	MEMO1	NM_001385196.1		c.875G>A	p.Arg292His	missense	Exon 8 of 10	NP_001372125.1
	MEMO1	NM_001371912.2		c.713G>A	p.Arg238His	missense	Exon 8 of 10	NP_001358841.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEMO1	ENST00000404530.6	TSL:2 MANE Select	c.593G>A	p.Arg198His	missense	Exon 8 of 10	ENSP00000385557.1	Q9Y316-1
	MEMO1	ENST00000379383.7	TSL:1	c.602G>A	p.Arg201His	missense	Exon 7 of 9	ENSP00000368691.3	Q9Y316-3
	MEMO1	ENST00000295065.9	TSL:1	c.593G>A	p.Arg198His	missense	Exon 7 of 9	ENSP00000295065.4	Q9Y316-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 231186 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000597

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1435626 Hom.: 0 Cov.: 28 AF XY: 0.00000561 AC XY: 4 AN XY: 713248

African (AFR) AF: 0.0000311 AC: 1 AN: 32182

American (AMR) AF: 0.00 AC: 0 AN: 40096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38624

South Asian (SAS) AF: 0.00 AC: 0 AN: 79664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1101050

Other (OTH) AF: 0.0000168 AC: 1 AN: 59426

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.0024
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.099
Sift	Benign	0.29	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.48		Loss of catalytic residue at R198 (P = 0.0865)
MVP		0.18
MPC		1.3
ClinPred		0.51	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.95
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs764340840; hg19: chr2-32108519; COSMIC: COSV99703844;