21-42076011-G-C

Variant names:

• chr21-42076011-G-C
• rs924433721
• NM_001004416.3:c.83G>C

Variant summary

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

The NM_001004416.3(UMODL1):​c.83G>C​(p.Gly28Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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 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	c.83G>C	p.Gly28Ala	missense_variant	Exon 2 of 23	ENST00000408910.7	NP_001004416.3
UMODL1	NM_173568.4	c.83G>C	p.Gly28Ala	missense_variant	Exon 2 of 22		NP_775839.4
UMODL1	NM_001199527.3	c.-134G>C		5_prime_UTR_variant	Exon 2 of 22		NP_001186456.2
UMODL1	NM_001199528.4	c.-134G>C		5_prime_UTR_variant	Exon 2 of 23		NP_001186457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMODL1	ENST00000408910.7	c.83G>C	p.Gly28Ala	missense_variant	Exon 2 of 23	1	NM_001004416.3	ENSP00000386147.2
UMODL1	ENST00000408989.6	c.83G>C	p.Gly28Ala	missense_variant	Exon 2 of 22	1		ENSP00000386126.2
UMODL1	ENST00000400427	c.-134G>C		5_prime_UTR_variant	Exon 2 of 22	1		ENSP00000383279.1
UMODL1	ENST00000400424	c.-134G>C		5_prime_UTR_variant	Exon 2 of 23	1		ENSP00000383276.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461236 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83G>C (p.G28A) alteration is located in exon 2 (coding exon 2) of the UMODL1 gene. This alteration results from a G to C substitution at nucleotide position 83, causing the glycine (G) at amino acid position 28 to be replaced by an alanine (A). 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	0.32
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.54
MutPred		0.49		Loss of catalytic residue at S30 (P = 0.1054);Loss of catalytic residue at S30 (P = 0.1054);
MVP		0.84
MPC		0.48
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.63
gMVP		0.53

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: rs924433721; hg19: chr21-43496120;