chr10-19387624-A-G

Variant names:

• chr10-19387624-A-G
• rs12773592
• NM_001142308.3:c.4538A>G

Variant summary

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

The NM_001142308.3(MALRD1):​c.4538A>G​(p.Asp1513Gly) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,549,940 control chromosomes in the GnomAD database, including 15,268 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1091 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14177 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.60

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=0.0024554431).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4538A>G	p.Asp1513Gly	missense_variant	Exon 27 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4538A>G	p.Asp1513Gly	missense_variant	Exon 27 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.2465A>G	p.Asp822Gly	missense_variant	Exon 13 of 25	5		ENSP00000366477.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17527 AN: 151960 Hom.: 1093 Cov.: 31

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0966

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0952

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.122 AC: 18281 AN: 149300 AF XY: 0.127

Gnomad AFR exome AF: 0.0777

Gnomad AMR exome AF: 0.0650

Gnomad ASJ exome AF: 0.0956

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.139 AC: 193839 AN: 1397862 Hom.: 14177 Cov.: 32 AF XY: 0.140 AC XY: 96418 AN XY: 689466

African (AFR) AF: 0.0741 AC: 2339 AN: 31586

American (AMR) AF: 0.0681 AC: 2431 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 2345 AN: 25176

East Asian (EAS) AF: 0.111 AC: 3963 AN: 35730

South Asian (SAS) AF: 0.168 AC: 13343 AN: 79224

European-Finnish (FIN) AF: 0.0981 AC: 4726 AN: 48174

Middle Eastern (MID) AF: 0.103 AC: 587 AN: 5700

European-Non Finnish (NFE) AF: 0.145 AC: 156466 AN: 1078574

Other (OTH) AF: 0.132 AC: 7639 AN: 57994

GnomAD4 genome AF: 0.115 AC: 17530 AN: 152078 Hom.: 1091 Cov.: 31 AF XY: 0.114 AC XY: 8440 AN XY: 74324

African (AFR) AF: 0.0762 AC: 3164 AN: 41506

American (AMR) AF: 0.0965 AC: 1473 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3468

East Asian (EAS) AF: 0.142 AC: 734 AN: 5164

South Asian (SAS) AF: 0.167 AC: 804 AN: 4804

European-Finnish (FIN) AF: 0.0952 AC: 1007 AN: 10582

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9612 AN: 67972

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.133 Hom.: 2593

Bravo AF: 0.113

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.146 AC: 562

ExAC AF: 0.122 AC: 2478

Asia WGS AF: 0.153 AC: 531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.086
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.97	T
PhyloP100		6.6
PROVEAN	Uncertain	-3.8	.;D
REVEL	Pathogenic	0.77
Sift	Benign	0.078	.;T
Sift4G	Uncertain	0.014	D;D
Vest4		0.23
ClinPred		0.020	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.91
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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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Other links and lift over

dbSNP: rs12773592; hg19: chr10-19676553; COSMIC: COSV65989009;