chr10-19491622-A-G

Variant names:

• chr10-19491622-A-G
• rs35934077
• NM_001142308.3:c.5135A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_001142308.3(MALRD1):​c.5135A>G​(p.Asp1712Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0125 in 1,549,642 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.013 (152 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.89
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-19491622-A-G is Benign according to our data. Variant chr10-19491622-A-G is described in ClinVar as [Benign]. Clinvar id is 770763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.5135A>G	p.Asp1712Gly	missense_variant	Exon 30 of 40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.5135A>G	p.Asp1712Gly	missense_variant	Exon 30 of 40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.3272A>G	p.Asp1091Gly	missense_variant	Exon 17 of 25	5		ENSP00000366477.3
MALRD1	ENST00000377265.3	c.185A>G	p.Asp62Gly	missense_variant	Exon 2 of 12	2		ENSP00000366476.3
MALRD1	ENST00000492202.1	n.185A>G		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1748 AN: 152136 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.0111 AC: 1662 AN: 149238 AF XY: 0.0106

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.0126 AC: 17646 AN: 1397390 Hom.: 152 Cov.: 32 AF XY: 0.0123 AC XY: 8460 AN XY: 689268

African (AFR) AF: 0.00149 AC: 47 AN: 31586

American (AMR) AF: 0.00294 AC: 105 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 351 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.00126 AC: 100 AN: 79228

European-Finnish (FIN) AF: 0.0409 AC: 1951 AN: 47662

Middle Eastern (MID) AF: 0.00456 AC: 26 AN: 5696

European-Non Finnish (NFE) AF: 0.0134 AC: 14473 AN: 1078664

Other (OTH) AF: 0.0102 AC: 593 AN: 57980

GnomAD4 genome AF: 0.0115 AC: 1748 AN: 152252 Hom.: 26 Cov.: 33 AF XY: 0.0126 AC XY: 937 AN XY: 74452

African (AFR) AF: 0.00217 AC: 90 AN: 41556

American (AMR) AF: 0.00811 AC: 124 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.0514 AC: 545 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 899 AN: 68006

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.0112 Hom.: 7

Bravo AF: 0.00806

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0174 AC: 67

ExAC AF: 0.00930 AC: 191

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Benign	0.063
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.87	T
PhyloP100		6.9
PROVEAN	Pathogenic	-4.6	.;D
REVEL	Uncertain	0.58
Sift	Benign	0.088	.;T
Sift4G	Pathogenic	0.0	D;T
Vest4		0.86
ClinPred		0.046	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.85
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35934077; hg19: chr10-19780551; COSMIC: COSV106544796; COSMIC: COSV106544796;