dbSNP rs10826986: MALRD1:p.Thr469Ala (chr10-19136775-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001142308.3(MALRD1):c.1405A>G(p.Thr469Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,231,184 control chromosomes in the GnomAD database, including 7,104 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 0.096 ( 757 hom., cov: 32)

Exomes 𝑓: 0.11 ( 6347 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.261

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034471452).

BP6

Variant 10-19136775-A-G is Benign according to our data. Variant chr10-19136775-A-G is described in ClinVar as [Benign]. Clinvar id is 771883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3 link	c.1405A>G	p.Thr469Ala	missense_variant	Exon 10 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.1405A>G	p.Thr469Ala	missense_variant	Exon 10 of 40	1	NM_001142308.3	ENSP00000412763.3		Q5VYJ5

Frequencies

GnomAD3 genomes

AF:

0.0964

AC:

14666

AN:

152084

Hom.:

758

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0995

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0710

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0374

Gnomad FIN

AF:

0.0909

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.0933

GnomAD4 exome

AF:

0.106

AC:

113965

AN:

1078982

Hom.:

6347

Cov.:

AF XY:

0.106

AC XY:

53995

AN XY:

509348

show subpopulations

Gnomad4 AFR exome

AF:

0.104

Gnomad4 AMR exome

AF:

0.0651

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0327

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.0928

GnomAD4 genome

AF:

0.0963

AC:

14661

AN:

152202

Hom.:

757

Cov.:

AF XY:

0.0919

AC XY:

6842

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0994

Gnomad4 AMR

AF:

0.0708

Gnomad4 ASJ

AF:

0.108

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0364

Gnomad4 FIN

AF:

0.0909

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.0919

Alfa

AF:

0.105

Hom.:

952

Bravo

AF:

0.0953

TwinsUK

AF:

0.109

AC:

406

ALSPAC

AF:

0.107

AC:

414

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.84

CADD

Benign

7.8

DANN

Benign

0.47

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0034

Sift4G

Benign

0.13

Vest4

0.051

MVP

0.085

GERP RS

0.032

Varity_R

0.055

gMVP

0.043

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over