Genetic Variant NM_001142308.3:c.5135A>T (chr10-19491622-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001142308.3(MALRD1):c.5135A>T(p.Asp1712Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,397,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1712G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.89

Publications

5 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.5135A>T	p.Asp1712Val	missense_variant	Exon 30 of 40	ENST00000454679.7	NP_001135780.2	Q5VYJ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MALRD1	ENST00000454679.7 link	c.5135A>T	p.Asp1712Val	missense_variant	Exon 30 of 40	1	NM_001142308.3	ENSP00000412763.3	Q5VYJ5
MALRD1	ENST00000377266.7 link	c.3272A>T	p.Asp1091Val	missense_variant	Exon 17 of 25	5		ENSP00000366477.3	U5GXS0
MALRD1	ENST00000377265.3 link	c.185A>T	p.Asp62Val	missense_variant	Exon 2 of 12	2		ENSP00000366476.3	H0Y3D6
MALRD1	ENST00000492202.1 link	n.185A>T		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000670

AC:

AN:

149238

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000928

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31586

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35710

South Asian (SAS)

AF:

0.00

AC:

AN:

79228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078728

Other (OTH)

AF:

0.00

AC:

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.063

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.81

PhyloP100

6.9

PROVEAN

Pathogenic

-6.2

.;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.014

.;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.88

MVP

0.81

ClinPred

0.83

GERP RS

5.1

Varity_R

0.19

gMVP

0.88

Mutation Taster

=92/8

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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NM_001142308.3:c.5135A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over