10-19595335-G-T

Position:

• chr10-19595335-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142308.3(MALRD1):​c.5822G>T​(p.Ser1941Ile) 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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1941N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19061089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.5822G>T	p.Ser1941Ile	missense_variant	34/40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.5822G>T	p.Ser1941Ile	missense_variant	34/40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.3959G>T	p.Ser1320Ile	missense_variant	21/25	5		ENSP00000366477.3
MALRD1	ENST00000377265.3	c.872G>T	p.Ser291Ile	missense_variant	6/12	2		ENSP00000366476.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	0.00054	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.6
DANN	Benign	0.92
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.34	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.22	D
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.12
Sift	Uncertain	0.016	.;D
Sift4G	Benign	0.097	T;T
Vest4		0.17
MVP		0.69
ClinPred		0.12	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.61

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: rs10827628; hg19: chr10-19884264;