chr10-19128279-G-A

Variant names:

• chr10-19128279-G-A
• rs78076387
• NM_001142308.3:c.1002G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142308.3(MALRD1):​c.1002G>A​(p.Arg334Arg) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.892
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -21 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.1002G>A	p.Arg334Arg	synonymous_variant	Exon 8 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.1002G>A	p.Arg334Arg	synonymous_variant	Exon 8 of 40	1	NM_001142308.3	ENSP00000412763.3

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

African (AFR) AF: 0.129 AC: 2971 AN: 23014

American (AMR) AF: 0.0685 AC: 577 AN: 8424

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 1166 AN: 14384

East Asian (EAS) AF: 0.000604 AC: 16 AN: 26498

South Asian (SAS) AF: 0.0193 AC: 377 AN: 19584

European-Finnish (FIN) AF: 0.0903 AC: 1904 AN: 21096

Middle Eastern (MID) AF: 0.0914 AC: 415 AN: 4540

European-Non Finnish (NFE) AF: 0.0688 AC: 63272 AN: 919624

Other (OTH) AF: 0.0668 AC: 2929 AN: 43830

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

African (AFR) AF: 0.126 AC: 5213 AN: 41532

American (AMR) AF: 0.0745 AC: 1137 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 255 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4832

European-Finnish (FIN) AF: 0.103 AC: 1092 AN: 10572

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0700 AC: 4759 AN: 67980

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0789 Hom.: 181

Bravo AF: 0.0842

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		-0.89

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

Other links and lift over

dbSNP: rs78076387; hg19: chr10-19417208; COSMIC: COSV107988536;