Genetic Variant MALRD1:p.Arg334Arg (chr10-19128279-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001142308.3(MALRD1):c.1002G>A(p.Arg334Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 1,233,156 control chromosomes in the GnomAD database, including 3,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 657 hom., cov: 33)

Exomes 𝑓: 0.068 ( 2699 hom. )

Consequence

MALRD1
NM_001142308.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.892

Variant links:

Genes affected

MALRD1 (HGNC:24331): (MAM and LDL receptor class A domain containing 1) This gene encodes a conserved protein that features multiple MAM (meprin-A5-protein tyrosine phosphatase mu) and LDLR A2 (low density lipoprotein receptor A2) domains. Expression of this gene is enriched in the small intestine and is upregulated during differentiation of a human cell line that exhibits properties of intestinal epithelial cells. The encoded protein has been shown to modulate production of FGF19 in a human intestinal cell line and may regulate bile acid metabolism in the liver. A synergistic interaction between an allele of this gene and the APOE E4 allele is associated with an elevated risk of Alzheimer's disease in human patients. [provided by RefSeq, Jul 2017]

MALRD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-19128279-G-A is Benign according to our data. Variant chr10-19128279-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 768351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.892 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.1002G>A	p.Arg334Arg	synonymous_variant	Exon 8 of 40	ENST00000454679.7	NP_001135780.2	Q5VYJ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7 link	c.1002G>A	p.Arg334Arg	synonymous_variant	Exon 8 of 40	1	NM_001142308.3	ENSP00000412763.3		Q5VYJ5

Frequencies

GnomAD3 genomes

AF:

0.0840

AC:

12774

AN:

152044

Hom.:

657

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.0746

Gnomad ASJ

AF:

0.0734

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0190

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0700

Gnomad OTH

AF:

0.0846

GnomAD4 exome

AF:

0.0681

AC:

73627

AN:

1080994

Hom.:

2699

Cov.:

AF XY:

0.0676

AC XY:

34484

AN XY:

510360

show subpopulations

African (AFR)

AF:

0.129

AC:

2971

AN:

23014

American (AMR)

AF:

0.0685

AC:

577

AN:

8424

Ashkenazi Jewish (ASJ)

AF:

0.0811

AC:

1166

AN:

14384

East Asian (EAS)

AF:

0.000604

AC:

AN:

26498

South Asian (SAS)

AF:

0.0193

AC:

377

AN:

19584

European-Finnish (FIN)

AF:

0.0903

AC:

1904

AN:

21096

Middle Eastern (MID)

AF:

0.0914

AC:

415

AN:

4540

European-Non Finnish (NFE)

AF:

0.0688

AC:

63272

AN:

919624

Other (OTH)

AF:

0.0668

AC:

2929

AN:

43830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3174

6348

9521

12695

15869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0840

AC:

12785

AN:

152162

Hom.:

657

Cov.:

AF XY:

0.0844

AC XY:

6278

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.126

AC:

5213

AN:

41532

American (AMR)

AF:

0.0745

AC:

1137

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0734

AC:

255

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5186

South Asian (SAS)

AF:

0.0182

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.103

AC:

1092

AN:

10572

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0700

AC:

4759

AN:

67980

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

582

1164

1745

2327

2909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0789

Hom.:

181

Bravo

AF:

0.0842

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.9

(source)

DANN

Benign

0.63

PhyloP100

-0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-19128279-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over