rs12267418

Positions:

• chr10-19425625-G-A

Variant summary

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

The NM_001142308.3(MALRD1):​c.4846-24682G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,174 control chromosomes in the GnomAD database, including 3,571 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 0.18 (3571 hom., cov: 32)
• Consequence: MALRD1 NM_001142308.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.436

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4846-24682G>A		intron_variant		ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4846-24682G>A		intron_variant		1	NM_001142308.3	ENSP00000412763	P1
MALRD1	ENST00000377266.7	c.2952+36016G>A		intron_variant		5		ENSP00000366477

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26583 AN: 152056 Hom.: 3552 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.175 AC: 26651 AN: 152174 Hom.: 3571 Cov.: 32 AF XY: 0.169 AC XY: 12583 AN XY: 74422

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0670

Gnomad4 FIN AF: 0.0476

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.169

Alfa AF: 0.129 Hom.: 1601

Bravo AF: 0.192

Asia WGS AF: 0.0730 AC: 255 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.61
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12267418; hg19: chr10-19714554;