rs7100382

chr10-19331478-A-Cchr10-19331478-A-T

Variant summary

Our verdict is Benign. Variant got -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. 13/16 in silico tools predict 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.3797A>C	p.Asp1266Ala	missense_variant	24/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.3797A>C	p.Asp1266Ala	missense_variant	24/40	1	NM_001142308.3	P1
MALRD1	ENST00000377266.7	c.1724A>C	p.Asp575Ala	missense_variant	10/25	5

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

GnomAD3 exomes AF: 0.575 AC: 86297 AN: 150186 Hom.: 25226 AF XY: 0.569 AC XY: 45855 AN XY: 80574

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 SAS exome AF: 0.471

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

Gnomad4 AFR exome AF: 0.738

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.632

Gnomad4 EAS exome AF: 0.540

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.605

Gnomad4 OTH exome AF: 0.608

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

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.595

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.605

Gnomad4 OTH AF: 0.655

Alfa AF: 0.606 Hom.: 61158

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
MutationTaster	Benign	1.0	P
REVEL	Benign	0.26
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

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

Publications

LitVar

Other links and lift over

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