10-19136775-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001142308.3(MALRD1):c.1405A>G(p.Thr469Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,231,184 control chromosomes in the GnomAD database, including 7,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (757 hom., cov: 32)
  • Exomes 𝑓: 0.11 (6347 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.261

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034471452).
• BP6: Variant 10-19136775-A-G is Benign according to our data. Variant chr10-19136775-A-G is described in ClinVar as [Benign]. Clinvar id is 771883.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALRD1	NM_001142308.3	c.1405A>G	p.Thr469Ala	missense_variant	10/40	ENST00000454679.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALRD1	ENST00000454679.7	c.1405A>G	p.Thr469Ala	missense_variant	10/40	1	NM_001142308.3	P1

Frequencies

GnomAD3 genomes AF: 0.0964 AC: 14666 AN: 152084 Hom.: 758 Cov.: 32

Gnomad AFR AF: 0.0995

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0909

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0933

GnomAD4 exome AF: 0.106 AC: 113965 AN: 1078982 Hom.: 6347 Cov.: 31 AF XY: 0.106 AC XY: 53995 AN XY: 509348

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0651

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0327

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.0928

GnomAD4 genome AF: 0.0963 AC: 14661 AN: 152202 Hom.: 757 Cov.: 32 AF XY: 0.0919 AC XY: 6842 AN XY: 74424

Gnomad4 AFR AF: 0.0994

Gnomad4 AMR AF: 0.0708

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0364

Gnomad4 FIN AF: 0.0909

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.0919

Alfa AF: 0.105 Hom.: 952

Bravo AF: 0.0953

TwinsUK AF: 0.109 AC: 406

ALSPAC AF: 0.107 AC: 414

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	7.8
Dann	Benign	0.47
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0034	T
Sift4G	Benign	0.13	T
Vest4		0.051
MVP		0.085
GERP RS		0.032
Varity_R		0.055
gMVP		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs10826986; hg19: chr10-19425704;