NM_001142308.3:c.4923G>C

Variant names:

• chr10-19450384-G-C
• rs117117480
• NM_001142308.3:c.4923G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001142308.3(MALRD1):​c.4923G>C​(p.Leu1641Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,550,220 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: MALRD1 NM_001142308.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 0 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]

LOC102724082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-19450384-G-C is Benign according to our data. Variant chr10-19450384-G-C is described in ClinVar as [Benign]. Clinvar id is 785880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4923G>C	p.Leu1641Leu	synonymous_variant	Exon 29 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4923G>C	p.Leu1641Leu	synonymous_variant	Exon 29 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.2953-38576G>C		intron_variant	Intron 15 of 24	5		ENSP00000366477.3

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.00458 AC: 686 AN: 149662 AF XY: 0.00460

Gnomad AFR exome AF: 0.000875

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00322

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00933

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00565 AC: 7902 AN: 1397936 Hom.: 34 Cov.: 31 AF XY: 0.00557 AC XY: 3843 AN XY: 689468

African (AFR) AF: 0.000855 AC: 27 AN: 31590

American (AMR) AF: 0.00213 AC: 76 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 108 AN: 25176

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35720

South Asian (SAS) AF: 0.00283 AC: 224 AN: 79216

European-Finnish (FIN) AF: 0.00942 AC: 454 AN: 48180

Middle Eastern (MID) AF: 0.00128 AC: 7 AN: 5466

European-Non Finnish (NFE) AF: 0.00622 AC: 6714 AN: 1078896

Other (OTH) AF: 0.00502 AC: 291 AN: 57990

GnomAD4 genome AF: 0.00496 AC: 756 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74468

African (AFR) AF: 0.000987 AC: 41 AN: 41554

American (AMR) AF: 0.00523 AC: 80 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00710 AC: 483 AN: 68026

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00488 Hom.: 1

Bravo AF: 0.00418

Asia WGS AF: 0.000289 AC: 1 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 17, 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	-0.71
CADD	Benign	0.26
DANN	Benign	0.52
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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: rs117117480; hg19: chr10-19739313;