NM_016406.4:c.247G>A

Variant names:

• chr1-161157309-G-A
• rs139173256
• NM_016406.4:c.247G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP3 BP4

The NM_016406.4(UFC1):​c.247G>A​(p.Glu83Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: UFC1 NM_016406.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 7.90
• Publications: 2 publications found

Genes affected

UFC1 (HGNC:26941): (ubiquitin-fold modifier conjugating enzyme 1) UFC1 is an E2-like conjugating enzyme for ubiquitin-fold modifier-1 (UFM1; MIM 610553) (Komatsu et al., 2004 [PubMed 15071506]).[supplied by OMIM, Mar 2008]

UFC1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with spasticity and poor growth

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000224985 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.23442 (below the threshold of 3.09). Trascript score misZ: 0.76313 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with spasticity and poor growth.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.26698375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016406.4. 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
	UFC1	NM_016406.4	MANE Select	c.247G>A	p.Glu83Lys	missense	Exon 3 of 6	NP_057490.2	Q9Y3C8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UFC1	ENST00000368003.6	TSL:1 MANE Select	c.247G>A	p.Glu83Lys	missense	Exon 3 of 6	ENSP00000356982.5	Q9Y3C8
	UFC1	ENST00000482672.1	TSL:1	n.446G>A		non_coding_transcript_exon	Exon 2 of 2
	UFC1	ENST00000913804.1		c.247G>A	p.Glu83Lys	missense	Exon 4 of 7	ENSP00000583863.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251488 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727242

African (AFR) AF: 0.00191 AC: 64 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1112004

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74356

African (AFR) AF: 0.00159 AC: 66 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	UFC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.72
MVP		0.83
MPC		0.41
ClinPred		0.20	T
GERP RS		5.3
Varity_R		0.66
gMVP		0.77
Mutation Taster		=9/91	disease causing

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: rs139173256; hg19: chr1-161127099; COSMIC: COSV99237515; COSMIC: COSV99237515;