NM_001004416.3:c.1252C>G

Variant names:

• chr21-42102231-C-G
• rs376085533
• NM_001004416.3:c.1252C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004416.3(UMODL1):​c.1252C>G​(p.Arg418Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R418C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.431
• Publications: 0 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]

UMODL1-AS1 (HGNC:23821): (UMODL1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0899615).

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.1252C>G	p.Arg418Gly	missense	Exon 8 of 23	NP_001004416.3	Q5DID0-1
	UMODL1	NM_173568.4		c.1252C>G	p.Arg418Gly	missense	Exon 8 of 22	NP_775839.4
	UMODL1	NM_001199527.3		c.1036C>G	p.Arg346Gly	missense	Exon 8 of 22	NP_001186456.2	Q5DID0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMODL1	ENST00000408910.7	TSL:1 MANE Select	c.1252C>G	p.Arg418Gly	missense	Exon 8 of 23	ENSP00000386147.2	Q5DID0-1
	UMODL1	ENST00000408989.6	TSL:1	c.1252C>G	p.Arg418Gly	missense	Exon 8 of 22	ENSP00000386126.2	Q5DID0-2
	UMODL1	ENST00000400427.5	TSL:1	c.1036C>G	p.Arg346Gly	missense	Exon 8 of 22	ENSP00000383279.1	Q5DID0-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461498 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.3
DANN	Benign	0.48
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.43
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.093
Sift	Benign	0.54	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.60		Loss of ubiquitination at K414 (P = 0.0566)
MVP		0.10
MPC		0.24
ClinPred		0.20	T
GERP RS		-0.0021
Varity_R		0.091
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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: rs376085533; hg19: chr21-43522341;