rs747359907

chr13-38349764-TTCA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000454060.2(LINC00571):n.322+171_322+173del variant causes a intron, non coding transcript 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: LINC00571 ENST00000454060.2 intron, non_coding_transcript
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.21

Genes affected

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

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-38349764-TTCA-T is Pathogenic according to our data. Variant chr13-38349764-TTCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38349764-TTCA-T is described in Lovd as [Pathogenic]. Variant chr13-38349764-TTCA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LINC00571	ENST00000454060.2	n.322+171_322+173del		intron_variant, non_coding_transcript_variant		3
LINC00571	ENST00000451826.2	n.322+171_322+173del		intron_variant, non_coding_transcript_variant		2
LINC00571	ENST00000700975.1	n.304+171_304+173del		intron_variant, non_coding_transcript_variant

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

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: 0.000217

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000170

Gnomad4 OTH exome AF: 0.0000409

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukodystrophy, hypomyelinating, 14 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Sep 30, 2020	This variant is located in the promoter region of UFM1 and has been previously reported as a homozygous change in sixteen patients with hypomyelination with atrophy of the basal ganglia and cerebellum (PMID: 28931644). Most of the patients were from Roma population, and the carrier frequency was as high as 25% in Eastern Slovakia (PMID: 28931644), suggesting a founder effect. In-vitro functional studies using a luciferase assay showed that this variant leads to reduced promoter activity in CNS-derived cell lines (PMID: 28931644). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.-273_-271delTCA variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 09, 2022	PS3, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 28, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3. This variant was detected in homozygous state. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 13, 2023	Criteria applied: PS3,PM3,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Sep 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	UFM1: PM3:Very Strong, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Apr 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs747359907; hg19: chr13-38923901;