chr10-19347940-G-T

Position:

• chr10-19347940-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000454679.7(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. 10/16 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 0.55 (23134 hom., cov: 31)
  • Exomes 𝑓: 0.57 (227957 hom.)
• Consequence: MALRD1 ENST00000454679.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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=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/exons	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4071G>T	p.Lys1357Asn	missense_variant	25/40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4071G>T	p.Lys1357Asn	missense_variant	25/40	1	NM_001142308.3	ENSP00000412763	P1
MALRD1	ENST00000377266.7	c.1998G>T	p.Lys666Asn	missense_variant	11/25	5		ENSP00000366477

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

GnomAD3 exomes AF: 0.540 AC: 80359 AN: 148798 Hom.: 22037 AF XY: 0.536 AC XY: 42936 AN XY: 80062

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 SAS exome AF: 0.440

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

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.613

Gnomad4 EAS exome AF: 0.540

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.597

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.569

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

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.578

Alfa AF: 0.575 Hom.: 32118

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
MutationTaster	Benign	0.95	P
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

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: rs1609746; hg19: chr10-19636869; COSMIC: COSV65990883;