21-42127678-T-C

Variant names:

• chr21-42127678-T-C
• rs220158
• NM_001004416.3:c.3537T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001004416.3(UMODL1):​c.3537T>C​(p.Pro1179Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,613,138 control chromosomes in the GnomAD database, including 643,911 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1179P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.86 (56556 hom., cov: 32)
  • Exomes 𝑓: 0.90 (587355 hom.)
• Consequence: UMODL1 NM_001004416.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.46
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP7: Synonymous conserved (PhyloP=-4.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004416.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMODL1	NM_001004416.3	MANE Select	c.3537T>C	p.Pro1179Pro	synonymous	Exon 20 of 23	NP_001004416.3
	UMODL1	NM_173568.4		c.3921T>C	p.Pro1307Pro	synonymous	Exon 19 of 22	NP_775839.4
	UMODL1	NM_001199527.3		c.3705T>C	p.Pro1235Pro	synonymous	Exon 19 of 22	NP_001186456.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMODL1	ENST00000408910.7	TSL:1 MANE Select	c.3537T>C	p.Pro1179Pro	synonymous	Exon 20 of 23	ENSP00000386147.2
	UMODL1	ENST00000408989.6	TSL:1	c.3921T>C	p.Pro1307Pro	synonymous	Exon 19 of 22	ENSP00000386126.2
	UMODL1	ENST00000400427.5	TSL:1	c.3705T>C	p.Pro1235Pro	synonymous	Exon 19 of 22	ENSP00000383279.1

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130783 AN: 152050 Hom.: 56528 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.877

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.867

GnomAD2 exomes AF: 0.875 AC: 217320 AN: 248258 AF XY: 0.876

Gnomad AFR exome AF: 0.779

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.969

Gnomad EAS exome AF: 0.781

Gnomad FIN exome AF: 0.866

Gnomad NFE exome AF: 0.911

Gnomad OTH exome AF: 0.895

GnomAD4 exome AF: 0.896 AC: 1308627 AN: 1460970 Hom.: 587355 Cov.: 57 AF XY: 0.894 AC XY: 649946 AN XY: 726784

African (AFR) AF: 0.777 AC: 25990 AN: 33432

American (AMR) AF: 0.881 AC: 39218 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 25252 AN: 26108

East Asian (EAS) AF: 0.779 AC: 30895 AN: 39680

South Asian (SAS) AF: 0.821 AC: 70605 AN: 86038

European-Finnish (FIN) AF: 0.868 AC: 46296 AN: 53360

Middle Eastern (MID) AF: 0.933 AC: 5381 AN: 5768

European-Non Finnish (NFE) AF: 0.910 AC: 1011213 AN: 1111706

Other (OTH) AF: 0.891 AC: 53777 AN: 60370

GnomAD4 genome AF: 0.860 AC: 130867 AN: 152168 Hom.: 56556 Cov.: 32 AF XY: 0.855 AC XY: 63595 AN XY: 74384

African (AFR) AF: 0.781 AC: 32424 AN: 41494

American (AMR) AF: 0.877 AC: 13422 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3331 AN: 3472

East Asian (EAS) AF: 0.775 AC: 4009 AN: 5176

South Asian (SAS) AF: 0.801 AC: 3862 AN: 4820

European-Finnish (FIN) AF: 0.862 AC: 9108 AN: 10572

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61749 AN: 68020

Other (OTH) AF: 0.864 AC: 1821 AN: 2108

Alfa AF: 0.887 Hom.: 91143

Bravo AF: 0.859

Asia WGS AF: 0.784 AC: 2729 AN: 3478

EpiCase AF: 0.917

EpiControl AF: 0.920

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.19
DANN	Benign	0.34
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs220158; hg19: chr21-43547788; COSMIC: COSV68570265; COSMIC: COSV68570265;