chr21-42076196-G-A

Position:

• chr21-42076196-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004416.3(UMODL1):​c.268G>A​(p.Val90Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11079064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMODL1	NM_001004416.3	c.268G>A	p.Val90Met	missense_variant	2/23	ENST00000408910.7
UMODL1	NM_173568.4	c.268G>A	p.Val90Met	missense_variant	2/22
UMODL1	NM_001199527.3	c.52G>A	p.Val18Met	missense_variant	2/22
UMODL1	NM_001199528.4	c.52G>A	p.Val18Met	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMODL1	ENST00000408910.7	c.268G>A	p.Val90Met	missense_variant	2/23	1	NM_001004416.3	P2
UMODL1	ENST00000408989.6	c.268G>A	p.Val90Met	missense_variant	2/22	1		A2
UMODL1	ENST00000400427.5	c.52G>A	p.Val18Met	missense_variant	2/22	1		A2
UMODL1	ENST00000400424.6	c.52G>A	p.Val18Met	missense_variant	2/23	1		A2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000361 AC: 90 AN: 249532 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000689

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.000133 AC XY: 97 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74516

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000619 AC: 75

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.268G>A (p.V90M) 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 268, causing the valine (V) at amino acid position 90 to be replaced by a methionine (M). 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	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	.;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	.;.;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.080	T;T;T;T
Sift4G	Uncertain	0.045	D;T;T;T
Polyphen		1.0, 1.0	.;.;D;D
Vest4		0.48
MVP		0.66
MPC		0.41
ClinPred		0.093	T
GERP RS		1.4
Varity_R		0.027
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs201393334; hg19: chr21-43496305;