chr6-96526340-G-A

Variant names:

• chr6-96526340-G-A
• rs1474358439
• NM_015323.5:c.370G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015323.5(UFL1):​c.370G>A​(p.Ala124Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A124S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UFL1 NM_015323.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015323.5. 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
	UFL1	NM_015323.5	MANE Select	c.370G>A	p.Ala124Thr	missense	Exon 5 of 19	NP_056138.1	O94874-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UFL1	ENST00000369278.5	TSL:1 MANE Select	c.370G>A	p.Ala124Thr	missense	Exon 5 of 19	ENSP00000358283.4	O94874-1
	UFL1	ENST00000863356.1		c.367G>A	p.Ala123Thr	missense	Exon 5 of 19	ENSP00000533415.1
	UFL1	ENST00000863355.1		c.370G>A	p.Ala124Thr	missense	Exon 5 of 19	ENSP00000533414.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460850 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726730

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86058

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111572

Other (OTH) AF: 0.00 AC: 0 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0706630), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.92	P
Vest4		0.69
MutPred		0.57		Gain of phosphorylation at A124 (P = 0.0592)
MVP		0.49
MPC		0.61
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.57
gMVP		0.74
Mutation Taster		=55/45	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: rs1474358439; hg19: chr6-96974216;