10-19128252-T-C

Variant names:

• chr10-19128252-T-C
• rs11008573
• NM_001142308.3:c.975T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142308.3(MALRD1):​c.975T>C​(p.Gly325Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,232,914 control chromosomes in the GnomAD database, including 19,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1676 hom., cov: 33)
  • Exomes 𝑓: 0.18 (18272 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.165
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-19128252-T-C is Benign according to our data. Variant chr10-19128252-T-C is described in ClinVar as [Benign]. Clinvar id is 769770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.975T>C	p.Gly325Gly	synonymous_variant	Exon 8 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.975T>C	p.Gly325Gly	synonymous_variant	Exon 8 of 40	1	NM_001142308.3	ENSP00000412763.3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20285 AN: 152126 Hom.: 1673 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.180 AC: 194624 AN: 1080670 Hom.: 18272 Cov.: 31 AF XY: 0.181 AC XY: 92103 AN XY: 510194

African (AFR) AF: 0.0381 AC: 877 AN: 23018

American (AMR) AF: 0.139 AC: 1169 AN: 8424

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 2277 AN: 14376

East Asian (EAS) AF: 0.115 AC: 3057 AN: 26496

South Asian (SAS) AF: 0.165 AC: 3224 AN: 19572

European-Finnish (FIN) AF: 0.135 AC: 2848 AN: 21096

Middle Eastern (MID) AF: 0.217 AC: 986 AN: 4540

European-Non Finnish (NFE) AF: 0.188 AC: 172930 AN: 919336

Other (OTH) AF: 0.166 AC: 7256 AN: 43812

GnomAD4 genome AF: 0.133 AC: 20285 AN: 152244 Hom.: 1676 Cov.: 33 AF XY: 0.131 AC XY: 9720 AN XY: 74454

African (AFR) AF: 0.0415 AC: 1726 AN: 41572

American (AMR) AF: 0.139 AC: 2124 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 556 AN: 3468

East Asian (EAS) AF: 0.100 AC: 518 AN: 5178

South Asian (SAS) AF: 0.160 AC: 773 AN: 4828

European-Finnish (FIN) AF: 0.126 AC: 1339 AN: 10612

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12669 AN: 67994

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.176 Hom.: 5123

Bravo AF: 0.129

Asia WGS AF: 0.121 AC: 420 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.96
DANN	Benign	0.43
PhyloP100		-0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11008573; hg19: chr10-19417181; COSMIC: COSV67685373;