chr21-42076147-G-A

Position:

chr21-42076147-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The ENST00000400427.5(UMODL1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

UMODL1
ENST00000400427.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UMODL1	NM_001004416.3 linkuse as main transcript	c.219G>A	p.Met73Ile	missense_variant	2/23	ENST00000408910.7
UMODL1	NM_001199527.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/22
UMODL1	NM_001199528.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/23
UMODL1	NM_173568.4 linkuse as main transcript	c.219G>A	p.Met73Ile	missense_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMODL1	ENST00000400427.5 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/22	1		A2	Q5DID0-4
UMODL1	ENST00000400424.6 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/23	1		A2	Q5DID0-3
UMODL1	ENST00000408910.7 linkuse as main transcript	c.219G>A	p.Met73Ile	missense_variant	2/23	1	NM_001004416.3	P2	Q5DID0-1
UMODL1	ENST00000408989.6 linkuse as main transcript	c.219G>A	p.Met73Ile	missense_variant	2/22	1		A2	Q5DID0-2

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

249560

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000185

AC:

270

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000240

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.219G>A (p.M73I) alteration is located in exon 2 (coding exon 2) of the UMODL1 gene. This alteration results from a G to A substitution at nucleotide position 219, causing the methionine (M) at amino acid position 73 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.10

DANN

Benign

0.82

DEOGEN2

Benign

0.014

.;.;.;T

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0056

LIST_S2

Uncertain

0.90

D;D;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;.;N;N

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.46

N;N;N;N

REVEL

Benign

0.098

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.0020, 0.0010

.;.;B;B

Vest4

0.35

MutPred

0.51

.;.;Gain of methylation at K72 (P = 0.0287);Gain of methylation at K72 (P = 0.0287);

MVP

0.014

MPC

0.11

ClinPred

0.072

GERP RS

-8.9

Varity_R

0.19

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over