10-19103996-A-G

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.615A>G(p.Gln205=) 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, single submitter B:1
• 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

Verdict is Benign. Variant got -15 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_single_submitter, 1 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/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.615A>G	p.Gln205=	synonymous_variant	5/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.615A>G	p.Gln205=	synonymous_variant	5/40	1	NM_001142308.3	P1

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

Gnomad4 AFR exome AF: 0.0878

Gnomad4 AMR exome AF: 0.0635

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.0426

Gnomad4 NFE exome AF: 0.0406

Gnomad4 OTH exome AF: 0.0612

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

Gnomad4 AFR AF: 0.0890

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.0801

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0395

Gnomad4 OTH AF: 0.0583

Alfa AF: 0.0454 Hom.: 37

Bravo AF: 0.0658

Asia WGS AF: 0.162 AC: 563 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

Jun 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	2.7
Dann	Benign	0.69

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