chr10-19331478-A-C

Variant names:

• chr10-19331478-A-C
• rs7100382
• NM_001142308.3:c.3797A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142308.3(MALRD1):​c.3797A>C​(p.Asp1266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,549,768 control chromosomes in the GnomAD database, including 282,934 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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 0.63 (30761 hom., cov: 32)
  • Exomes 𝑓: 0.60 (252173 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7240454E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.3797A>C	p.Asp1266Ala	missense_variant	Exon 24 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.3797A>C	p.Asp1266Ala	missense_variant	Exon 24 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.1724A>C	p.Asp575Ala	missense_variant	Exon 10 of 25	5		ENSP00000366477.3

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96008 AN: 151802 Hom.: 30736 Cov.: 32

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.659

GnomAD2 exomes AF: 0.575 AC: 86297 AN: 150186 AF XY: 0.569

Gnomad AFR exome AF: 0.728

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.631

Gnomad EAS exome AF: 0.502

Gnomad FIN exome AF: 0.624

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.598 AC: 836269 AN: 1397848 Hom.: 252173 Cov.: 43 AF XY: 0.594 AC XY: 409806 AN XY: 689442

African (AFR) AF: 0.738 AC: 23303 AN: 31586

American (AMR) AF: 0.542 AC: 19342 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 15910 AN: 25170

East Asian (EAS) AF: 0.540 AC: 19302 AN: 35716

South Asian (SAS) AF: 0.471 AC: 37295 AN: 79224

European-Finnish (FIN) AF: 0.615 AC: 29656 AN: 48242

Middle Eastern (MID) AF: 0.675 AC: 3846 AN: 5696

European-Non Finnish (NFE) AF: 0.605 AC: 652342 AN: 1078476

Other (OTH) AF: 0.608 AC: 35273 AN: 58036

GnomAD4 genome AF: 0.632 AC: 96086 AN: 151920 Hom.: 30761 Cov.: 32 AF XY: 0.630 AC XY: 46793 AN XY: 74232

African (AFR) AF: 0.726 AC: 30092 AN: 41462

American (AMR) AF: 0.595 AC: 9076 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2221 AN: 3464

East Asian (EAS) AF: 0.514 AC: 2638 AN: 5132

South Asian (SAS) AF: 0.456 AC: 2198 AN: 4818

European-Finnish (FIN) AF: 0.625 AC: 6592 AN: 10554

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41110 AN: 67932

Other (OTH) AF: 0.655 AC: 1387 AN: 2116

Alfa AF: 0.611 Hom.: 99244

Bravo AF: 0.635

TwinsUK AF: 0.611 AC: 2264

ALSPAC AF: 0.580 AC: 2237

ExAC AF: 0.548 AC: 10902

Asia WGS AF: 0.480 AC: 1669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.31
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.030	T;T
MetaRNN	Benign	0.0000037	T;T
MetaSVM	Benign	-0.88	T
PhyloP100		2.3
PROVEAN	Benign	2.1	.;N
REVEL	Benign	0.26
Sift	Benign	0.91	.;T
Sift4G	Benign	0.48	T;T
Vest4		0.041
ClinPred		0.0045	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs7100382; hg19: chr10-19620407; COSMIC: COSV65990871;