21-42071353-G-C

Variant names:

• chr21-42071353-G-C
• rs1380527196
• NM_001004416.3:c.37G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004416.3(UMODL1):​c.37G>C​(p.Val13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V13F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: UMODL1 NM_001004416.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0626086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMODL1	NM_001004416.3	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 23	ENST00000408910.7	NP_001004416.3
UMODL1	NM_173568.4	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 22		NP_775839.4
UMODL1	NM_001199527.3	c.-140-4652G>C		intron_variant	Intron 1 of 21		NP_001186456.2
UMODL1	NM_001199528.4	c.-140-4652G>C		intron_variant	Intron 1 of 22		NP_001186457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMODL1	ENST00000408910.7	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 23	1	NM_001004416.3	ENSP00000386147.2
UMODL1	ENST00000408989.6	c.37G>C	p.Val13Leu	missense_variant	Exon 1 of 22	1		ENSP00000386126.2
UMODL1	ENST00000400427.5	c.-140-4652G>C		intron_variant	Intron 1 of 21	1		ENSP00000383279.1
UMODL1	ENST00000400424.6	c.-140-4652G>C		intron_variant	Intron 1 of 22	1		ENSP00000383276.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.0
DANN	Benign	0.66
DEOGEN2	Benign	0.0039	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N
PhyloP100		0.34
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.046
Sift	Benign	0.36	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0050	B;B
Vest4		0.087
MutPred		0.42		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.26
MPC		0.16
ClinPred		0.042	T
GERP RS		0.47
PromoterAI		0.0012	Neutral
Varity_R		0.050
gMVP		0.32
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1380527196; hg19: chr21-43491462;