Genetic Variant MALRD1:p.Asp1266Val (chr10-19331478-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001142308.3(MALRD1):c.3797A>T(p.Asp1266Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,550,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

19 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.188149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.3797A>T	p.Asp1266Val	missense_variant	Exon 24 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.3797A>T	p.Asp1266Val	missense_variant	Exon 24 of 40	1	NM_001142308.3	ENSP00000412763.3		Q5VYJ5
MALRD1	ENST00000377266.7 link	c.1724A>T	p.Asp575Val	missense_variant	Exon 10 of 25	5		ENSP00000366477.3		U5GXS0

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

150186

AF XY:

0.0000124

show subpopulations

Gnomad AFR exome

AF:

0.000143

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000644

AC:

AN:

1398180

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689594

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31588

American (AMR)

AF:

0.0000560

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35720

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078782

Other (OTH)

AF:

0.0000172

AC:

AN:

58040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151864

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

99244

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.52

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.091

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.19

T;T

MetaSVM

Pathogenic

0.86

PhyloP100

2.3

PROVEAN

Benign

0.24

.;N

REVEL

Uncertain

0.30

Sift

Benign

0.31

.;T

Sift4G

Benign

0.14

T;T

Vest4

0.22

MVP

0.78

ClinPred

0.031

GERP RS

5.3

Varity_R

0.053

gMVP

0.55

Mutation Taster

=97/3

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over