NM_001142308.3:c.1405A>G

Variant names:

• chr10-19136775-A-G
• rs10826986
• NM_001142308.3:c.1405A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.261
• Publications: 2 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: Benign. The variant received -20 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 VariationId is 771883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	NM_001142308.3	MANE Select	c.1405A>G	p.Thr469Ala	missense	Exon 10 of 40	NP_001135780.2	Q5VYJ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	ENST00000454679.7	TSL:1 MANE Select	c.1405A>G	p.Thr469Ala	missense	Exon 10 of 40	ENSP00000412763.3	Q5VYJ5

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

African (AFR) AF: 0.104 AC: 2398 AN: 22958

American (AMR) AF: 0.0651 AC: 548 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1491 AN: 14384

East Asian (EAS) AF: 0.000151 AC: 4 AN: 26522

South Asian (SAS) AF: 0.0327 AC: 638 AN: 19484

European-Finnish (FIN) AF: 0.106 AC: 2238 AN: 21096

Middle Eastern (MID) AF: 0.0944 AC: 275 AN: 2914

European-Non Finnish (NFE) AF: 0.111 AC: 102322 AN: 919548

Other (OTH) AF: 0.0928 AC: 4051 AN: 43660

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

African (AFR) AF: 0.0994 AC: 4129 AN: 41520

American (AMR) AF: 0.0708 AC: 1082 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4832

European-Finnish (FIN) AF: 0.0909 AC: 964 AN: 10604

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7573 AN: 68012

Other (OTH) AF: 0.0919 AC: 194 AN: 2112

Alfa AF: 0.105 Hom.: 1214

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.26
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

Other links and lift over

dbSNP: rs10826986; hg19: chr10-19425704;