21-42137588-A-C

Position:

• chr21-42137588-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004416.3(UMODL1):​c.3925A>C​(p.Asn1309His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,724 control chromosomes in the GnomAD database, including 29,240 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (2661 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26579 hom.)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056490004).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMODL1	NM_001004416.3	c.3925A>C	p.Asn1309His	missense_variant	22/23	ENST00000408910.7	NP_001004416.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMODL1	ENST00000408910.7	c.3925A>C	p.Asn1309His	missense_variant	22/23	1	NM_001004416.3	ENSP00000386147.2

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28386 AN: 151870 Hom.: 2657 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.208 AC: 51821 AN: 249476 Hom.: 5554 AF XY: 0.211 AC XY: 28502 AN XY: 135356

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.293

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.187 AC: 273843 AN: 1461736 Hom.: 26579 Cov.: 54 AF XY: 0.191 AC XY: 138776 AN XY: 727164

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.187 AC: 28393 AN: 151988 Hom.: 2661 Cov.: 32 AF XY: 0.189 AC XY: 14073 AN XY: 74288

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.174

Alfa AF: 0.181 Hom.: 6230

Bravo AF: 0.184

TwinsUK AF: 0.164 AC: 608

ALSPAC AF: 0.168 AC: 647

ESP6500AA AF: 0.157 AC: 640

ESP6500EA AF: 0.180 AC: 1507

ExAC AF: 0.208 AC: 25197

Asia WGS AF: 0.256 AC: 890 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0085	.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.054	T;D;T;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.68, 0.80	.;.;P;P
Vest4		0.096
MPC		0.41
ClinPred		0.013	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs3819142; hg19: chr21-43557698; COSMIC: COSV68569982;