Variant rs1609746 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001142308.3(MALRD1):c.4071G>T(p.Lys1357Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,549,902 control chromosomes in the GnomAD database, including 251,091 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.55 ( 23134 hom., cov: 31)

Exomes 𝑓: 0.57 ( 227957 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4290214E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.4071G>T	p.Lys1357Asn	missense_variant	Exon 25 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.4071G>T	p.Lys1357Asn	missense_variant	Exon 25 of 40	1	NM_001142308.3	ENSP00000412763.3		Q5VYJ5
MALRD1	ENST00000377266.7 link	c.1998G>T	p.Lys666Asn	missense_variant	Exon 11 of 25	5		ENSP00000366477.3		U5GXS0

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83355

AN:

151788

Hom.:

23126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.604

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.619

Gnomad EAS

AF:

0.510

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.612

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.581

GnomAD3 exomes

AF:

0.540

AC:

80359

AN:

148798

Hom.:

22037

AF XY:

0.536

AC XY:

42936

AN XY:

80062

show subpopulations

Gnomad AFR exome

AF:

0.485

Gnomad AMR exome

AF:

0.505

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.500

Gnomad SAS exome

AF:

0.440

Gnomad FIN exome

AF:

0.606

Gnomad NFE exome

AF:

0.579

Gnomad OTH exome

AF:

0.573

GnomAD4 exome

AF:

0.569

AC:

795267

AN:

1397996

Hom.:

227957

Cov.:

AF XY:

0.565

AC XY:

389921

AN XY:

689534

show subpopulations

Gnomad4 AFR exome

AF:

0.489

Gnomad4 AMR exome

AF:

0.509

Gnomad4 ASJ exome

AF:

0.613

Gnomad4 EAS exome

AF:

0.540

Gnomad4 SAS exome

AF:

0.439

Gnomad4 FIN exome

AF:

0.597

Gnomad4 NFE exome

AF:

0.581

Gnomad4 OTH exome

AF:

0.569

GnomAD4 genome

AF:

0.549

AC:

83399

AN:

151906

Hom.:

23134

Cov.:

AF XY:

0.550

AC XY:

40824

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.488

Gnomad4 AMR

AF:

0.553

Gnomad4 ASJ

AF:

0.619

Gnomad4 EAS

AF:

0.510

Gnomad4 SAS

AF:

0.427

Gnomad4 FIN

AF:

0.612

Gnomad4 NFE

AF:

0.581

Gnomad4 OTH

AF:

0.578

Alfa

AF:

0.575

Hom.:

32118

Bravo

AF:

0.542

TwinsUK

AF:

0.587

AC:

2175

ALSPAC

AF:

0.561

AC:

2163

ExAC

AF:

0.496

AC:

9719

Asia WGS

AF:

0.449

AC:

1563

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.044

Eigen_PC

Benign

0.069

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

T;D

MetaRNN

Benign

0.00014

T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.6

.;N

REVEL

Benign

0.076

Sift

Benign

0.28

.;T

Sift4G

Uncertain

0.010

D;D

Vest4

0.14

ClinPred

0.010

GERP RS

3.0

Varity_R

0.074

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over