21-42071360-C-T

Position:

• chr21-42071360-C-T

Variant summary

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

The NM_001004416.3(UMODL1):​c.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,444,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0670

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=0.14475402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMODL1	NM_001004416.3	c.44C>T	p.Ala15Val	missense_variant	1/23	ENST00000408910.7	NP_001004416.3
UMODL1	NM_173568.4	c.44C>T	p.Ala15Val	missense_variant	1/22		NP_775839.4
UMODL1	NM_001199527.3	c.-140-4645C>T		intron_variant			NP_001186456.2
UMODL1	NM_001199528.4	c.-140-4645C>T		intron_variant			NP_001186457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMODL1	ENST00000408910.7	c.44C>T	p.Ala15Val	missense_variant	1/23	1	NM_001004416.3	ENSP00000386147.2
UMODL1	ENST00000408989.6	c.44C>T	p.Ala15Val	missense_variant	1/22	1		ENSP00000386126.2
UMODL1	ENST00000400427.5	c.-140-4645C>T		intron_variant		1		ENSP00000383279.1
UMODL1	ENST00000400424.6	c.-140-4645C>T		intron_variant		1		ENSP00000383276.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444870 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 718306

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: 0.00000453

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Dec 10, 2024

The c.44C>T (p.A15V) alteration is located in exon 1 (coding exon 1) of the UMODL1 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the alanine (A) at amino acid position 15 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.097
DEOGEN2	Benign	0.0032	.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.026	D;T
Sift4G	Uncertain	0.049	D;T
Polyphen		0.88	P;P
Vest4		0.14
MutPred		0.40		Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);
MVP		0.67
MPC		0.35
ClinPred		0.17	T
GERP RS		2.6
Varity_R		0.035
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1317538524; hg19: chr21-43491469;