rs747359907

Variant names:

• chr13-38349764-TTCA-T
• rs747359907
• ENST00000451826.2:n.322+171_322+173delTGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The ENST00000451826.2(LINC00571):​n.322+171_322+173delTGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,279,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001984793: "In-vitro functional studies using a luciferase assay showed that this variant leads to reduced promoter activity in CNS-derived cell lines." PMID:28931644" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: LINC00571 ENST00000451826.2 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.21
• Publications: 2 publications found

Genes affected

LINC00571 (HGNC:43721): (long intergenic non-protein coding RNA 571)

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]

UFM1 Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hypomyelinating leukodystrophy 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001984793: "In-vitro functional studies using a luciferase assay showed that this variant leads to reduced promoter activity in CNS-derived cell lines." PMID:28931644; SCV006585474: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product." PMID: 28931644
• PP5: Variant 13-38349764-TTCA-T is Pathogenic according to our data. Variant chr13-38349764-TTCA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000451826.2. 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
	UFM1	NM_016617.4	MANE Select	c.-155_-153delTCA		upstream_gene	N/A	NP_057701.1	P61960-1
	UFM1	NM_001286704.2		c.-273_-271delTCA		upstream_gene	N/A	NP_001273633.1	P61960-2
	UFM1	NM_001286703.2		c.-155_-153delTCA		upstream_gene	N/A	NP_001273632.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINC00571	ENST00000451826.2	TSL:2	n.322+171_322+173delTGA		intron	N/A
	LINC00571	ENST00000454060.2	TSL:3	n.322+171_322+173delTGA		intron	N/A
	LINC00571	ENST00000700975.1		n.304+171_304+173delTGA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 32 AN: 1127316 Hom.: 0 AF XY: 0.0000351 AC XY: 20 AN XY: 569990

African (AFR) AF: 0.00 AC: 0 AN: 26778

American (AMR) AF: 0.00 AC: 0 AN: 40340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21234

East Asian (EAS) AF: 0.00 AC: 0 AN: 37950

South Asian (SAS) AF: 0.000217 AC: 16 AN: 73876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3574

European-Non Finnish (NFE) AF: 0.0000170 AC: 14 AN: 825514

Other (OTH) AF: 0.0000409 AC: 2 AN: 48844

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Leukodystrophy, hypomyelinating, 14 (11)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs747359907;

hg19: chr13-38923901;