chr10-19347940-G-T

Variant names:

• chr10-19347940-G-T
• rs1609746
• NM_001142308.3:c.4071G>T

Variant summary

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

The NM_001142308.3(MALRD1):​c.4071G>T​(p.Lys1357Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,549,902 control chromosomes in the GnomAD database, including 251,091 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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 0.55 (23134 hom., cov: 31)
  • Exomes 𝑓: 0.57 (227957 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 14 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=1.4290214E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4071G>T	p.Lys1357Asn	missense_variant	Exon 25 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4071G>T	p.Lys1357Asn	missense_variant	Exon 25 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.1998G>T	p.Lys666Asn	missense_variant	Exon 11 of 25	5		ENSP00000366477.3

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83355 AN: 151788 Hom.: 23126 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.581

GnomAD2 exomes AF: 0.540 AC: 80359 AN: 148798 AF XY: 0.536

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.505

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.500

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.569 AC: 795267 AN: 1397996 Hom.: 227957 Cov.: 52 AF XY: 0.565 AC XY: 389921 AN XY: 689534

African (AFR) AF: 0.489 AC: 15450 AN: 31584

American (AMR) AF: 0.509 AC: 18172 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 15435 AN: 25174

East Asian (EAS) AF: 0.540 AC: 19278 AN: 35732

South Asian (SAS) AF: 0.439 AC: 34799 AN: 79226

European-Finnish (FIN) AF: 0.597 AC: 28765 AN: 48168

Middle Eastern (MID) AF: 0.585 AC: 3333 AN: 5694

European-Non Finnish (NFE) AF: 0.581 AC: 627025 AN: 1078730

Other (OTH) AF: 0.569 AC: 33010 AN: 57988

GnomAD4 genome AF: 0.549 AC: 83399 AN: 151906 Hom.: 23134 Cov.: 31 AF XY: 0.550 AC XY: 40824 AN XY: 74222

African (AFR) AF: 0.488 AC: 20210 AN: 41412

American (AMR) AF: 0.553 AC: 8453 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2147 AN: 3468

East Asian (EAS) AF: 0.510 AC: 2621 AN: 5138

South Asian (SAS) AF: 0.427 AC: 2051 AN: 4798

European-Finnish (FIN) AF: 0.612 AC: 6470 AN: 10566

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39504 AN: 67936

Other (OTH) AF: 0.578 AC: 1220 AN: 2110

Alfa AF: 0.568 Hom.: 41112

Bravo AF: 0.542

TwinsUK AF: 0.587 AC: 2175

ALSPAC AF: 0.561 AC: 2163

ExAC AF: 0.496 AC: 9719

Asia WGS AF: 0.449 AC: 1563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.044
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;D
MetaRNN	Benign	0.00014	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.076
Sift	Benign	0.28	.;T
Sift4G	Uncertain	0.010	D;D
Vest4		0.14
ClinPred		0.010	T
GERP RS		3.0
Varity_R		0.074
gMVP		0.39
Mutation Taster		=71/29	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: rs1609746; hg19: chr10-19636869; COSMIC: COSV65990883;