10-19595335-G-C

Variant names:

• chr10-19595335-G-C
• rs10827628
• NM_001142308.3:c.5822G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142308.3(MALRD1):​c.5822G>C​(p.Ser1941Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 11 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09920755).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	NM_001142308.3	MANE Select	c.5822G>C	p.Ser1941Thr	missense	Exon 34 of 40	NP_001135780.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	ENST00000454679.7	TSL:1 MANE Select	c.5822G>C	p.Ser1941Thr	missense	Exon 34 of 40	ENSP00000412763.3
	MALRD1	ENST00000377266.7	TSL:5	c.3959G>C	p.Ser1320Thr	missense	Exon 21 of 25	ENSP00000366477.3
	MALRD1	ENST00000377265.3	TSL:2	c.872G>C	p.Ser291Thr	missense	Exon 6 of 12	ENSP00000366476.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151742 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000663 AC: 1 AN: 150730 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 60

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151742 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74048

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.6
DANN	Benign	0.73
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.24	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.099	T
MetaSVM	Uncertain	0.22	D
PhyloP100		1.6
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	0.97	T
Vest4		0.064
MVP		0.44
ClinPred		0.034	T
GERP RS		3.3
Varity_R		0.052
gMVP		0.48
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs10827628; hg19: chr10-19884264;