chr10-19165786-G-A

Variant names:

• chr10-19165786-G-A
• rs78786296
• NM_001142308.3:c.1806G>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.1806G>A​(p.Ala602Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,231,356 control chromosomes in the GnomAD database, including 2,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (291 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2157 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300
• Publications: 0 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=-0.73).
• BP6: Variant 10-19165786-G-A is Benign according to our data. Variant chr10-19165786-G-A is described in ClinVar as [Benign]. Clinvar id is 769363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.1806G>A	p.Ala602Ala	synonymous_variant	Exon 13 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.1806G>A	p.Ala602Ala	synonymous_variant	Exon 13 of 40	1	NM_001142308.3	ENSP00000412763.3

Frequencies

GnomAD3 genomes AF: 0.0578 AC: 8792 AN: 151996 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0616

Gnomad OTH AF: 0.0793

GnomAD4 exome AF: 0.0615 AC: 66333 AN: 1079242 Hom.: 2157 Cov.: 30 AF XY: 0.0613 AC XY: 31209 AN XY: 509438

African (AFR) AF: 0.0737 AC: 1692 AN: 22962

American (AMR) AF: 0.0574 AC: 483 AN: 8418

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 1291 AN: 14388

East Asian (EAS) AF: 0.0000754 AC: 2 AN: 26514

South Asian (SAS) AF: 0.0172 AC: 335 AN: 19488

European-Finnish (FIN) AF: 0.0289 AC: 610 AN: 21096

Middle Eastern (MID) AF: 0.0731 AC: 213 AN: 2914

European-Non Finnish (NFE) AF: 0.0642 AC: 59074 AN: 919796

Other (OTH) AF: 0.0603 AC: 2633 AN: 43666

GnomAD4 genome AF: 0.0578 AC: 8792 AN: 152114 Hom.: 291 Cov.: 32 AF XY: 0.0552 AC XY: 4102 AN XY: 74352

African (AFR) AF: 0.0687 AC: 2850 AN: 41504

American (AMR) AF: 0.0613 AC: 936 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 297 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4820

European-Finnish (FIN) AF: 0.0241 AC: 255 AN: 10582

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0616 AC: 4189 AN: 67986

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0620 Hom.: 60

Bravo AF: 0.0620

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.73
CADD	Benign	3.7
DANN	Benign	0.78
PhyloP100		-0.0030

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: rs78786296; hg19: chr10-19454715;