13-38358115-G-A

Position:

• chr13-38358115-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016617.4(UFM1):​c.140G>A​(p.Ser47Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UFM1 NM_016617.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.97

Genes affected

UFM1 (HGNC:20597): (ubiquitin fold modifier 1) UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBA5 (UBE1DC1; MIM 610552) and E2-like conjugating enzyme UFC1 (MIM 610554) in a manner analogous to ubiquitylation (see UBE2M; MIM 603173) (Komatsu et al., 2004 [PubMed 15071506]).[supplied by OMIM, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UFM1	NM_016617.4	c.140G>A	p.Ser47Asn	missense_variant	4/6	ENST00000239878.9	NP_057701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UFM1	ENST00000239878.9	c.140G>A	p.Ser47Asn	missense_variant	4/6	1	NM_016617.4	ENSP00000239878.4
UFM1	ENST00000379649.5	c.194G>A	p.Ser65Asn	missense_variant	4/6	4		ENSP00000368970.1
UFM1	ENST00000437952.1	c.140G>A	p.Ser47Asn	missense_variant	3/4	3		ENSP00000402378.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1291838 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 641414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 65 of the UFM1 protein (p.Ser65Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UFM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1027884). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Leukodystrophy, hypomyelinating, 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 21, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.00087	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.0046	T
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.53		.;Gain of catalytic residue at S47 (P = 0);
MVP		0.41
MPC		1.2
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1879200093; hg19: chr13-38932252;