6-96536334-A-G

Variant names:

• chr6-96536334-A-G
• rs151296506
• NM_015323.5:c.746A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015323.5(UFL1):​c.746A>G​(p.Tyr249Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UFL1 NM_015323.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.60

Genes affected

UFL1 (HGNC:23039): (UFM1 specific ligase 1) Enables UFM1 ligase activity and protein kinase binding activity. Involved in several processes, including cellular protein modification process; regulation of signal transduction; and reticulophagy. Acts upstream of or within several processes, including positive regulation of cell population proliferation; regulation of proteasomal ubiquitin-dependent protein catabolic process; and response to endoplasmic reticulum stress. Located in endoplasmic reticulum membrane; nucleus; and site of double-strand break. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UFL1	NM_015323.5	c.746A>G	p.Tyr249Cys	missense_variant	Exon 8 of 19	ENST00000369278.5	NP_056138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UFL1	ENST00000369278.5	c.746A>G	p.Tyr249Cys	missense_variant	Exon 8 of 19	1	NM_015323.5	ENSP00000358283.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251008 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135684

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459484 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726040

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746A>G (p.Y249C) alteration is located in exon 8 (coding exon 8) of the UFL1 gene. This alteration results from a A to G substitution at nucleotide position 746, causing the tyrosine (Y) at amino acid position 249 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.54
MPC		0.75
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.79
gMVP		0.92

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: rs151296506; hg19: chr6-96984210;