10-19523038-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142308.3(MALRD1):c.5321-8156G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.036 in 152,204 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.036 (180 hom., cov: 32)
• Consequence: MALRD1 NM_001142308.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.5321-8156G>C		intron_variant		ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.5321-8156G>C		intron_variant		1	NM_001142308.3	P1
MALRD1	ENST00000377265.3	c.372-8156G>C		intron_variant		2
MALRD1	ENST00000377266.7	c.3458-8156G>C		intron_variant		5
MALRD1	ENST00000492202.1	n.449-8156G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5459 AN: 152086 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0259

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0360 AC: 5472 AN: 152204 Hom.: 180 Cov.: 32 AF XY: 0.0347 AC XY: 2584 AN XY: 74444

Gnomad4 AFR AF: 0.0908

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0257

Alfa AF: 0.00918 Hom.: 2

Bravo AF: 0.0399

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.75
Dann	Benign	0.58

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: rs10494863; hg19: chr10-19811967;