10-19203773-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001142308.3(MALRD1):c.1997C>T(p.Ala666Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,549,776 control chromosomes in the GnomAD database, including 16,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1378 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15025 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017303824).
• BP6: Variant 10-19203773-C-T is Benign according to our data. Variant chr10-19203773-C-T is described in ClinVar as [Benign]. Clinvar id is 769364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.1997C>T	p.Ala666Val	missense_variant	15/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.1997C>T	p.Ala666Val	missense_variant	15/40	1	NM_001142308.3	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19739 AN: 151976 Hom.: 1375 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.141 AC: 197280 AN: 1397682 Hom.: 15025 Cov.: 32 AF XY: 0.139 AC XY: 95560 AN XY: 689314

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0991

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.000308

Gnomad4 SAS exome AF: 0.0629

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.130 AC: 19752 AN: 152094 Hom.: 1378 Cov.: 32 AF XY: 0.126 AC XY: 9336 AN XY: 74356

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.169

Alfa AF: 0.150 Hom.: 2067

Bravo AF: 0.132

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.147 AC: 565

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Benign	0.64
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0017	T
Sift4G	Benign	0.60	T
Vest4		0.071
MVP		0.12
GERP RS		3.4
Varity_R		0.057
gMVP		0.058

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: rs16918344; hg19: chr10-19492702;