chr10-19498489-T-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

The NM_001142308.3(MALRD1):​c.5163T>G​(p.His1721Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,548,422 control chromosomes in the GnomAD database, including 39,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8967 hom., cov: 32)
Exomes 𝑓: 0.20 ( 30205 hom. )

Consequence

MALRD1
NM_001142308.3 missense

Scores

1
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.743

Publications

14 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MALRD1NM_001142308.3 linkc.5163T>G p.His1721Gln missense_variant Exon 31 of 40 ENST00000454679.7 NP_001135780.2 Q5VYJ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MALRD1ENST00000454679.7 linkc.5163T>G p.His1721Gln missense_variant Exon 31 of 40 1 NM_001142308.3 ENSP00000412763.3 Q5VYJ5
MALRD1ENST00000377266.7 linkc.3300T>G p.His1100Gln missense_variant Exon 18 of 25 5 ENSP00000366477.3 U5GXS0
MALRD1ENST00000377265.3 linkc.213T>G p.His71Gln missense_variant Exon 3 of 12 2 ENSP00000366476.3 H0Y3D6
MALRD1ENST00000492202.1 linkn.291T>G non_coding_transcript_exon_variant Exon 4 of 5 4

Frequencies

GnomAD3 genomes
AF:
0.298
AC:
45285
AN:
151908
Hom.:
8950
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.568
Gnomad AMI
AF:
0.350
Gnomad AMR
AF:
0.212
Gnomad ASJ
AF:
0.339
Gnomad EAS
AF:
0.238
Gnomad SAS
AF:
0.208
Gnomad FIN
AF:
0.168
Gnomad MID
AF:
0.253
Gnomad NFE
AF:
0.182
Gnomad OTH
AF:
0.284
GnomAD2 exomes
AF:
0.224
AC:
33290
AN:
148786
AF XY:
0.222
show subpopulations
Gnomad AFR exome
AF:
0.576
Gnomad AMR exome
AF:
0.208
Gnomad ASJ exome
AF:
0.341
Gnomad EAS exome
AF:
0.258
Gnomad FIN exome
AF:
0.171
Gnomad NFE exome
AF:
0.186
Gnomad OTH exome
AF:
0.215
GnomAD4 exome
AF:
0.197
AC:
274844
AN:
1396396
Hom.:
30205
Cov.:
31
AF XY:
0.197
AC XY:
135346
AN XY:
688614
show subpopulations
African (AFR)
AF:
0.582
AC:
18366
AN:
31552
American (AMR)
AF:
0.211
AC:
7508
AN:
35642
Ashkenazi Jewish (ASJ)
AF:
0.347
AC:
8715
AN:
25122
East Asian (EAS)
AF:
0.209
AC:
7476
AN:
35710
South Asian (SAS)
AF:
0.206
AC:
16342
AN:
79172
European-Finnish (FIN)
AF:
0.174
AC:
8382
AN:
48144
Middle Eastern (MID)
AF:
0.267
AC:
1519
AN:
5692
European-Non Finnish (NFE)
AF:
0.180
AC:
193407
AN:
1077472
Other (OTH)
AF:
0.227
AC:
13129
AN:
57890
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
9595
19190
28785
38380
47975
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
7132
14264
21396
28528
35660
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.298
AC:
45345
AN:
152026
Hom.:
8967
Cov.:
32
AF XY:
0.292
AC XY:
21689
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.568
AC:
23543
AN:
41424
American (AMR)
AF:
0.212
AC:
3238
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.339
AC:
1174
AN:
3466
East Asian (EAS)
AF:
0.238
AC:
1230
AN:
5162
South Asian (SAS)
AF:
0.207
AC:
1000
AN:
4822
European-Finnish (FIN)
AF:
0.168
AC:
1783
AN:
10588
Middle Eastern (MID)
AF:
0.255
AC:
75
AN:
294
European-Non Finnish (NFE)
AF:
0.182
AC:
12391
AN:
67988
Other (OTH)
AF:
0.281
AC:
592
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1434
2867
4301
5734
7168
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
424
848
1272
1696
2120
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.227
Hom.:
15299
Bravo
AF:
0.319
TwinsUK
AF:
0.187
AC:
695
ALSPAC
AF:
0.175
AC:
676
ExAC
AF:
0.220
AC:
4233
Asia WGS
AF:
0.216
AC:
750
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
14
DANN
Benign
0.60
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.053
T;T
MetaRNN
Benign
0.000090
T;T
MetaSVM
Benign
-0.93
T
PhyloP100
-0.74
PROVEAN
Benign
-0.11
.;N
REVEL
Uncertain
0.31
Sift
Benign
0.35
.;T
Sift4G
Benign
0.53
T;T
Vest4
0.017
ClinPred
0.0015
T
GERP RS
-1.6
Varity_R
0.025
gMVP
0.11
Mutation Taster
=95/5
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.62
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.62
Position offset: 1

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

Publications

Other links and lift over

dbSNP: rs12256835; hg19: chr10-19787418; COSMIC: COSV65974448; API