10-19103996-A-G

Variant names:

• chr10-19103996-A-G
• rs57243552
• NM_001142308.3:c.615A>G

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.615A>G​(p.Gln205Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,233,286 control chromosomes in the GnomAD database, including 2,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (479 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2491 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.221

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=-0.58).
• BP6: Variant 10-19103996-A-G is Benign according to our data. Variant chr10-19103996-A-G is described in ClinVar as [Benign]. Clinvar id is 771739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.615A>G	p.Gln205Gln	synonymous_variant	Exon 5 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.615A>G	p.Gln205Gln	synonymous_variant	Exon 5 of 40	1	NM_001142308.3	ENSP00000412763.3

Frequencies

GnomAD3 genomes AF: 0.0640 AC: 9723 AN: 152030 Hom.: 481 Cov.: 32

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.0792

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0590

GnomAD4 exome AF: 0.0494 AC: 53405 AN: 1081138 Hom.: 2491 Cov.: 30 AF XY: 0.0491 AC XY: 25037 AN XY: 510422

African (AFR) AF: 0.0878 AC: 2020 AN: 23010

American (AMR) AF: 0.0635 AC: 535 AN: 8422

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 319 AN: 14388

East Asian (EAS) AF: 0.305 AC: 8083 AN: 26488

South Asian (SAS) AF: 0.0673 AC: 1318 AN: 19580

European-Finnish (FIN) AF: 0.0426 AC: 898 AN: 21098

Middle Eastern (MID) AF: 0.0372 AC: 169 AN: 4542

European-Non Finnish (NFE) AF: 0.0406 AC: 37378 AN: 919768

Other (OTH) AF: 0.0612 AC: 2685 AN: 43842

GnomAD4 genome AF: 0.0640 AC: 9742 AN: 152148 Hom.: 479 Cov.: 32 AF XY: 0.0661 AC XY: 4920 AN XY: 74384

African (AFR) AF: 0.0890 AC: 3695 AN: 41520

American (AMR) AF: 0.0530 AC: 810 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1422 AN: 5170

South Asian (SAS) AF: 0.0801 AC: 386 AN: 4820

European-Finnish (FIN) AF: 0.0503 AC: 533 AN: 10588

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0395 AC: 2684 AN: 67988

Other (OTH) AF: 0.0583 AC: 123 AN: 2108

Alfa AF: 0.0462 Hom.: 66

Bravo AF: 0.0658

Asia WGS AF: 0.162 AC: 563 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 06, 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	-0.58
CADD	Benign	2.7
DANN	Benign	0.69
PhyloP100		0.22

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

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Other links and lift over

dbSNP: rs57243552; hg19: chr10-19392925; COSMIC: COSV67685371;