Genetic Variant UMODL1:p.Gly28Asp (chr21-42076011-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001004416.3(UMODL1):c.83G>A(p.Gly28Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,236 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G28A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

UMODL1
NM_001004416.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.44

Publications

0 publications found

Variant links:

Genes affected

UMODL1 (HGNC:12560): (uromodulin like 1) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in neutrophil migration. Predicted to act upstream of or within several processes, including adipose tissue development; cellular response to gonadotropin-releasing hormone; and regulation of ovarian follicle development. Predicted to be located in cytoplasm and external side of plasma membrane. Predicted to be integral component of membrane. Predicted to be active in apical plasma membrane; cell surface; and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

UMODL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMODL1	NM_001004416.3 link	c.83G>A	p.Gly28Asp	missense_variant	Exon 2 of 23	ENST00000408910.7	NP_001004416.3	Q5DID0-1
UMODL1	NM_173568.4 link	c.83G>A	p.Gly28Asp	missense_variant	Exon 2 of 22		NP_775839.4	Q5DID0-2
UMODL1	NM_001199527.3 link	c.-134G>A		5_prime_UTR_variant	Exon 2 of 22		NP_001186456.2	Q5DID0-4
UMODL1	NM_001199528.4 link	c.-134G>A		5_prime_UTR_variant	Exon 2 of 23		NP_001186457.3	Q5DID0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UMODL1	ENST00000408910.7 link	c.83G>A	p.Gly28Asp	missense_variant	Exon 2 of 23	1	NM_001004416.3	ENSP00000386147.2	Q5DID0-1
UMODL1	ENST00000408989.6 link	c.83G>A	p.Gly28Asp	missense_variant	Exon 2 of 22	1		ENSP00000386126.2	Q5DID0-2
UMODL1	ENST00000400427.5 link	c.-134G>A		5_prime_UTR_variant	Exon 2 of 22	1		ENSP00000383279.1	Q5DID0-4
UMODL1	ENST00000400424.6 link	c.-134G>A		5_prime_UTR_variant	Exon 2 of 23	1		ENSP00000383276.1	Q5DID0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

247862

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461236

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111474

Other (OTH)

AF:

0.0000497

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

0.97

L;L

PhyloP100

4.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.48

Loss of catalytic residue at S30 (P = 0.0399);Loss of catalytic residue at S30 (P = 0.0399);

MVP

0.86

MPC

0.58

ClinPred

0.98

GERP RS

4.4

Varity_R

0.81

gMVP

0.53

Mutation Taster

=75/25

polymorphism

(source)

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

Publications

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chr21-42076011-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over