rs12779623

Variant names:

• chr10-19136602-A-G
• rs12779623
• NM_001142308.3:c.1232A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142308.3(MALRD1):​c.1232A>G​(p.Gln411Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,230,686 control chromosomes in the GnomAD database, including 25,877 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 0.17 (2803 hom., cov: 32)
  • Exomes 𝑓: 0.20 (23074 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015641153).
• BP6: Variant 10-19136602-A-G is Benign according to our data. Variant chr10-19136602-A-G is described in ClinVar as [Benign]. Clinvar id is 769362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.1232A>G	p.Gln411Arg	missense_variant	Exon 10 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.1232A>G	p.Gln411Arg	missense_variant	Exon 10 of 40	1	NM_001142308.3	ENSP00000412763.3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25579 AN: 152034 Hom.: 2800 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.203 AC: 219148 AN: 1078534 Hom.: 23074 Cov.: 30 AF XY: 0.204 AC XY: 103727 AN XY: 509104

African (AFR) AF: 0.0295 AC: 678 AN: 22960

American (AMR) AF: 0.292 AC: 2461 AN: 8418

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 3258 AN: 14388

East Asian (EAS) AF: 0.163 AC: 4331 AN: 26520

South Asian (SAS) AF: 0.122 AC: 2382 AN: 19472

European-Finnish (FIN) AF: 0.256 AC: 5409 AN: 21098

Middle Eastern (MID) AF: 0.147 AC: 427 AN: 2914

European-Non Finnish (NFE) AF: 0.209 AC: 191954 AN: 919118

Other (OTH) AF: 0.189 AC: 8248 AN: 43646

GnomAD4 genome AF: 0.168 AC: 25583 AN: 152152 Hom.: 2803 Cov.: 32 AF XY: 0.171 AC XY: 12757 AN XY: 74386

African (AFR) AF: 0.0398 AC: 1655 AN: 41542

American (AMR) AF: 0.253 AC: 3862 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3472

East Asian (EAS) AF: 0.145 AC: 750 AN: 5168

South Asian (SAS) AF: 0.118 AC: 568 AN: 4820

European-Finnish (FIN) AF: 0.270 AC: 2853 AN: 10558

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14680 AN: 67990

Other (OTH) AF: 0.159 AC: 336 AN: 2110

Alfa AF: 0.195 Hom.: 1434

Bravo AF: 0.162

TwinsUK AF: 0.211 AC: 781

ALSPAC AF: 0.207 AC: 797

Asia WGS AF: 0.142 AC: 493 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.86
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0016	T
PhyloP100		1.4
Sift4G	Uncertain	0.037	D
Vest4		0.077
MVP		0.15
GERP RS		2.7
Varity_R		0.034
gMVP		0.036

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

Other links and lift over

dbSNP: rs12779623; hg19: chr10-19425531; COSMIC: COSV107183508;