NM_001004416.3:c.3925A>C

Variant names:

• chr21-42137588-A-C
• rs3819142
• NM_001004416.3:c.3925A>C

Variant summary

Our verdict is Benign. The variant received -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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1309Y) has been classified as Uncertain significance.

• 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
• Publications: 22 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]

ENSG00000304334 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMODL1	NM_001004416.3	MANE Select	c.3925A>C	p.Asn1309His	missense	Exon 22 of 23	NP_001004416.3
	UMODL1	NM_173568.4		c.4309A>C	p.Asn1437His	missense	Exon 21 of 22	NP_775839.4
	UMODL1	NM_001199527.3		c.4093A>C	p.Asn1365His	missense	Exon 21 of 22	NP_001186456.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMODL1	ENST00000408910.7	TSL:1 MANE Select	c.3925A>C	p.Asn1309His	missense	Exon 22 of 23	ENSP00000386147.2
	UMODL1	ENST00000408989.6	TSL:1	c.4309A>C	p.Asn1437His	missense	Exon 21 of 22	ENSP00000386126.2
	UMODL1	ENST00000400427.5	TSL:1	c.4093A>C	p.Asn1365His	missense	Exon 21 of 22	ENSP00000383279.1

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

GnomAD2 exomes AF: 0.208 AC: 51821 AN: 249476 AF XY: 0.211

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 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

African (AFR) AF: 0.169 AC: 5660 AN: 33476

American (AMR) AF: 0.218 AC: 9733 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4721 AN: 26132

East Asian (EAS) AF: 0.222 AC: 8812 AN: 39698

South Asian (SAS) AF: 0.289 AC: 24922 AN: 86246

European-Finnish (FIN) AF: 0.226 AC: 12045 AN: 53384

Middle Eastern (MID) AF: 0.242 AC: 1395 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194867 AN: 1111926

Other (OTH) AF: 0.194 AC: 11688 AN: 60386

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

African (AFR) AF: 0.161 AC: 6657 AN: 41438

American (AMR) AF: 0.206 AC: 3140 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3466

East Asian (EAS) AF: 0.233 AC: 1197 AN: 5138

South Asian (SAS) AF: 0.302 AC: 1458 AN: 4820

European-Finnish (FIN) AF: 0.227 AC: 2398 AN: 10566

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12228 AN: 67982

Other (OTH) AF: 0.174 AC: 367 AN: 2104

Alfa AF: 0.181 Hom.: 8711

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 v4.9

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
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.68	P
Vest4		0.096
MPC		0.41
ClinPred		0.013	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.52
Mutation Taster		=99/1	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: rs3819142; hg19: chr21-43557698; COSMIC: COSV68569982;