chr21-42127763-G-A

Variant names:

• chr21-42127763-G-A
• rs220159
• NM_001004416.3:c.3622G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173568.4(UMODL1):​c.4006G>A​(p.Asp1336Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,798 control chromosomes in the GnomAD database, including 101,485 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.35 (9449 hom., cov: 33)
  • Exomes 𝑓: 0.35 (92036 hom.)
• Consequence: UMODL1 NM_173568.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.909
• Publications: 38 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004284829).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173568.4. 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.3622G>A	p.Asp1208Asn	missense	Exon 20 of 23	NP_001004416.3
	UMODL1	NM_173568.4		c.4006G>A	p.Asp1336Asn	missense	Exon 19 of 22	NP_775839.4
	UMODL1	NM_001199527.3		c.3790G>A	p.Asp1264Asn	missense	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.3622G>A	p.Asp1208Asn	missense	Exon 20 of 23	ENSP00000386147.2
	UMODL1	ENST00000408989.6	TSL:1	c.4006G>A	p.Asp1336Asn	missense	Exon 19 of 22	ENSP00000386126.2
	UMODL1	ENST00000400427.5	TSL:1	c.3790G>A	p.Asp1264Asn	missense	Exon 19 of 22	ENSP00000383279.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53069 AN: 151910 Hom.: 9433 Cov.: 33

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.355

GnomAD2 exomes AF: 0.369 AC: 92025 AN: 249488 AF XY: 0.368

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.354 AC: 516856 AN: 1461770 Hom.: 92036 Cov.: 49 AF XY: 0.353 AC XY: 256859 AN XY: 727186

African (AFR) AF: 0.304 AC: 10182 AN: 33474

American (AMR) AF: 0.438 AC: 19597 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10393 AN: 26134

East Asian (EAS) AF: 0.357 AC: 14166 AN: 39696

South Asian (SAS) AF: 0.357 AC: 30771 AN: 86236

European-Finnish (FIN) AF: 0.345 AC: 18426 AN: 53414

Middle Eastern (MID) AF: 0.403 AC: 2326 AN: 5768

European-Non Finnish (NFE) AF: 0.350 AC: 389385 AN: 1111940

Other (OTH) AF: 0.358 AC: 21610 AN: 60388

GnomAD4 genome AF: 0.349 AC: 53133 AN: 152028 Hom.: 9449 Cov.: 33 AF XY: 0.352 AC XY: 26132 AN XY: 74290

African (AFR) AF: 0.312 AC: 12909 AN: 41434

American (AMR) AF: 0.414 AC: 6336 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1378 AN: 3472

East Asian (EAS) AF: 0.381 AC: 1978 AN: 5186

South Asian (SAS) AF: 0.362 AC: 1739 AN: 4806

European-Finnish (FIN) AF: 0.345 AC: 3640 AN: 10538

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23884 AN: 67986

Other (OTH) AF: 0.356 AC: 752 AN: 2110

Alfa AF: 0.355 Hom.: 17527

Bravo AF: 0.354

TwinsUK AF: 0.341 AC: 1263

ALSPAC AF: 0.357 AC: 1375

ESP6500AA AF: 0.307 AC: 1242

ESP6500EA AF: 0.352 AC: 2939

ExAC AF: 0.365 AC: 44136

Asia WGS AF: 0.355 AC: 1234 AN: 3478

EpiCase AF: 0.359

EpiControl AF: 0.355

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.12
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.91
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.10
ClinPred		0.0023	T
GERP RS		2.4
Varity_R		0.031
gMVP		0.21
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: rs220159; hg19: chr21-43547873; COSMIC: COSV68569225; COSMIC: COSV68569225;