chr10-19615941-A-AT

Variant names:

• chr10-19615941-A-AT
• rs10580913
• NM_001142308.3:c.6137+29dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001142308.3(MALRD1):​c.6137+29dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0065 (0 hom.)
• Consequence: MALRD1 NM_001142308.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.6137+29dupT		intron_variant	Intron 36 of 39	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.6137+18_6137+19insT		intron_variant	Intron 36 of 39	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.4207+8039_4207+8040insT		intron_variant	Intron 22 of 24	5		ENSP00000366477.3
MALRD1	ENST00000377265.3	c.1187+18_1187+19insT		intron_variant	Intron 8 of 11	2		ENSP00000366476.3

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149870 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000978

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0107 AC: 1142 AN: 106568 AF XY: 0.0106

Gnomad AFR exome AF: 0.00758

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.00466

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00649 AC: 8321 AN: 1281688 Hom.: 0 Cov.: 0 AF XY: 0.00669 AC XY: 4219 AN XY: 630684

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00531 AC: 151 AN: 28436

American (AMR) AF: 0.0132 AC: 406 AN: 30680

Ashkenazi Jewish (ASJ) AF: 0.00825 AC: 184 AN: 22312

East Asian (EAS) AF: 0.00591 AC: 192 AN: 32512

South Asian (SAS) AF: 0.0137 AC: 936 AN: 68158

European-Finnish (FIN) AF: 0.00461 AC: 146 AN: 31642

Middle Eastern (MID) AF: 0.00401 AC: 21 AN: 5236

European-Non Finnish (NFE) AF: 0.00586 AC: 5919 AN: 1009476

Other (OTH) AF: 0.00688 AC: 366 AN: 53236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 149976 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73170

African (AFR) AF: 0.0000489 AC: 2 AN: 40926

American (AMR) AF: 0.00 AC: 0 AN: 15014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.0000978 AC: 1 AN: 10224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67294

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0120 Hom.: 1596

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10580913; hg19: chr10-19904870; COSMIC: COSV65981962;