Genetic Variant MALRD1:p.Phe586Val (chr10-19165736-T-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001142308.3(MALRD1):c.1756T>G(p.Phe586Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,231,686 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 34 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.944

Publications

0 publications found

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045844316).

BP6

Variant 10-19165736-T-G is Benign according to our data. Variant chr10-19165736-T-G is described in ClinVar as [Benign]. Clinvar id is 2640342.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.1756T>G	p.Phe586Val	missense_variant	Exon 13 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.1756T>G	p.Phe586Val	missense_variant	Exon 13 of 40	1	NM_001142308.3	ENSP00000412763.3		Q5VYJ5

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0646

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.00382

GnomAD4 exome

AF:

0.00242

AC:

2608

AN:

1079372

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

1272

AN XY:

509498

show subpopulations

African (AFR)

AF:

0.0000435

AC:

AN:

22966

American (AMR)

AF:

0.000950

AC:

AN:

8418

Ashkenazi Jewish (ASJ)

AF:

0.0624

AC:

897

AN:

14386

East Asian (EAS)

AF:

0.00

AC:

AN:

26514

South Asian (SAS)

AF:

0.00108

AC:

AN:

19492

European-Finnish (FIN)

AF:

0.000758

AC:

AN:

21098

Middle Eastern (MID)

AF:

0.00137

AC:

AN:

2914

European-Non Finnish (NFE)

AF:

0.00153

AC:

1412

AN:

919918

Other (OTH)

AF:

0.00570

AC:

249

AN:

43666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

136

272

409

545

681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152314

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

224

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00388

Hom.:

Bravo

AF:

0.00270

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MALRD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.11

(source)

DANN

Benign

0.36

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0046

PhyloP100

-0.94

Sift4G

Benign

0.21

Vest4

0.23

MVP

0.19

GERP RS

-5.3

Varity_R

0.084

gMVP

0.065

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

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chr10-19165736-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over