10-19128252-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001142308.3(MALRD1):c.975T>C(p.Gly325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,232,914 control chromosomes in the GnomAD database, including 19,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1676 hom., cov: 33)
  • Exomes 𝑓: 0.18 (18272 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-19128252-T-C is Benign according to our data. Variant chr10-19128252-T-C is described in ClinVar as [Benign]. Clinvar id is 769770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.975T>C	p.Gly325=	synonymous_variant	8/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.975T>C	p.Gly325=	synonymous_variant	8/40	1	NM_001142308.3	P1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20285 AN: 152126 Hom.: 1673 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.180 AC: 194624 AN: 1080670 Hom.: 18272 Cov.: 31 AF XY: 0.181 AC XY: 92103 AN XY: 510194

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.133 AC: 20285 AN: 152244 Hom.: 1676 Cov.: 33 AF XY: 0.131 AC XY: 9720 AN XY: 74454

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.157

Alfa AF: 0.178 Hom.: 3751

Bravo AF: 0.129

Asia WGS AF: 0.121 AC: 420 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

Apr 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.96
Dann	Benign	0.43

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: rs11008573; hg19: chr10-19417181; COSMIC: COSV67685373;