chr10-19498489-T-G

Variant names:

• chr10-19498489-T-G
• rs12256835
• NM_001142308.3:c.5163T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_001142308.3(MALRD1):​c.5163T>G​(p.His1721Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,548,422 control chromosomes in the GnomAD database, including 39,172 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.

• Frequency:
  • Genomes: 𝑓 0.30 (8967 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30205 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• 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 -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.5163T>G	p.His1721Gln	missense_variant	Exon 31 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.5163T>G	p.His1721Gln	missense_variant	Exon 31 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.3300T>G	p.His1100Gln	missense_variant	Exon 18 of 25	5		ENSP00000366477.3
MALRD1	ENST00000377265.3	c.213T>G	p.His71Gln	missense_variant	Exon 3 of 12	2		ENSP00000366476.3
MALRD1	ENST00000492202.1	n.291T>G		non_coding_transcript_exon_variant	Exon 4 of 5	4

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45285 AN: 151908 Hom.: 8950 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.224 AC: 33290 AN: 148786 AF XY: 0.222

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.258

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.197 AC: 274844 AN: 1396396 Hom.: 30205 Cov.: 31 AF XY: 0.197 AC XY: 135346 AN XY: 688614

African (AFR) AF: 0.582 AC: 18366 AN: 31552

American (AMR) AF: 0.211 AC: 7508 AN: 35642

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 8715 AN: 25122

East Asian (EAS) AF: 0.209 AC: 7476 AN: 35710

South Asian (SAS) AF: 0.206 AC: 16342 AN: 79172

European-Finnish (FIN) AF: 0.174 AC: 8382 AN: 48144

Middle Eastern (MID) AF: 0.267 AC: 1519 AN: 5692

European-Non Finnish (NFE) AF: 0.180 AC: 193407 AN: 1077472

Other (OTH) AF: 0.227 AC: 13129 AN: 57890

GnomAD4 genome AF: 0.298 AC: 45345 AN: 152026 Hom.: 8967 Cov.: 32 AF XY: 0.292 AC XY: 21689 AN XY: 74346

African (AFR) AF: 0.568 AC: 23543 AN: 41424

American (AMR) AF: 0.212 AC: 3238 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1174 AN: 3466

East Asian (EAS) AF: 0.238 AC: 1230 AN: 5162

South Asian (SAS) AF: 0.207 AC: 1000 AN: 4822

European-Finnish (FIN) AF: 0.168 AC: 1783 AN: 10588

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12391 AN: 67988

Other (OTH) AF: 0.281 AC: 592 AN: 2106

Alfa AF: 0.227 Hom.: 15299

Bravo AF: 0.319

TwinsUK AF: 0.187 AC: 695

ALSPAC AF: 0.175 AC: 676

ExAC AF: 0.220 AC: 4233

Asia WGS AF: 0.216 AC: 750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.60
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.053	T;T
MetaRNN	Benign	0.000090	T;T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.74
PROVEAN	Benign	-0.11	.;N
REVEL	Uncertain	0.31
Sift	Benign	0.35	.;T
Sift4G	Benign	0.53	T;T
Vest4		0.017
ClinPred		0.0015	T
GERP RS		-1.6
Varity_R		0.025
gMVP		0.11
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12256835; hg19: chr10-19787418; COSMIC: COSV65974448;