10-19128279-G-A

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.1002G>A(p.Arg334=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 1,233,156 control chromosomes in the GnomAD database, including 3,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (657 hom., cov: 33)
  • Exomes 𝑓: 0.068 (2699 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.892

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=-0.75).
• BP6: Variant 10-19128279-G-A is Benign according to our data. Variant chr10-19128279-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 768351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.1002G>A	p.Arg334=	synonymous_variant	8/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.1002G>A	p.Arg334=	synonymous_variant	8/40	1	NM_001142308.3	P1

Frequencies

GnomAD3 genomes AF: 0.0840 AC: 12774 AN: 152044 Hom.: 657 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.0846

GnomAD4 exome AF: 0.0681 AC: 73627 AN: 1080994 Hom.: 2699 Cov.: 31 AF XY: 0.0676 AC XY: 34484 AN XY: 510360

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.0811

Gnomad4 EAS exome AF: 0.000604

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0903

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0668

GnomAD4 genome AF: 0.0840 AC: 12785 AN: 152162 Hom.: 657 Cov.: 33 AF XY: 0.0844 AC XY: 6278 AN XY: 74388

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0745

Gnomad4 ASJ AF: 0.0734

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0700

Gnomad4 OTH AF: 0.0833

Alfa AF: 0.0801 Hom.: 111

Bravo AF: 0.0842

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	3.9
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78076387; hg19: chr10-19417208;