chr10-19595335-G-A

Position:

• chr10-19595335-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.5822G>A​(p.Ser1941Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,550,002 control chromosomes in the GnomAD database, including 207,126 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (19744 hom., cov: 30)
  • Exomes 𝑓: 0.52 (187382 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.011048E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.5822G>A	p.Ser1941Asn	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>A	p.Ser1941Asn	missense_variant	34/40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.3959G>A	p.Ser1320Asn	missense_variant	21/25	5		ENSP00000366477.3
MALRD1	ENST00000377265.3	c.872G>A	p.Ser291Asn	missense_variant	6/12	2		ENSP00000366476.3

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77162 AN: 151644 Hom.: 19733 Cov.: 30

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.488

GnomAD3 exomes AF: 0.466 AC: 70277 AN: 150730 Hom.: 16942 AF XY: 0.467 AC XY: 37696 AN XY: 80802

Gnomad AFR exome AF: 0.534

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.365

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.515 AC: 720707 AN: 1398238 Hom.: 187382 Cov.: 60 AF XY: 0.512 AC XY: 352838 AN XY: 689642

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.443

Gnomad4 EAS exome AF: 0.422

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome AF: 0.509 AC: 77210 AN: 151764 Hom.: 19744 Cov.: 30 AF XY: 0.505 AC XY: 37458 AN XY: 74124

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.560

Gnomad4 NFE AF: 0.529

Gnomad4 OTH AF: 0.486

Alfa AF: 0.517 Hom.: 40851

Bravo AF: 0.499

TwinsUK AF: 0.542 AC: 2011

ALSPAC AF: 0.535 AC: 2062

ExAC AF: 0.430 AC: 8957

Asia WGS AF: 0.415 AC: 1445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.6
DANN	Benign	0.97
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.000090	T;T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-0.64	.;N
REVEL	Benign	0.043
Sift	Benign	0.053	.;T
Sift4G	Benign	0.27	T;T
Vest4		0.033
ClinPred		0.0042	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV63196343; COSMIC: COSV63196343;