12-120291839-T-TA

Position:

• chr12-120291839-T-TA

Variant summary

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

The NM_001385733.1(SIRT4):​c.-1105_-1104insA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIRT4 NM_001385733.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.81

Genes affected

SIRT4 (HGNC:14932): (sirtuin 4) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family. [provided by RefSeq, Jul 2008]

RNU4-2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120291839-T-TA is Pathogenic according to our data. Variant chr12-120291839-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 3068742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT4	NM_001385733.1	c.-1105_-1104insA		5_prime_UTR_variant	1/4		NP_001372662.1
SIRT4	NM_001385735.1	c.-1105_-1104insA		5_prime_UTR_variant	1/4		NP_001372664.1
SIRT4	XM_006719309.5	c.-1457_-1456insA		5_prime_UTR_variant	1/4		XP_006719372.1
RNU4-2	NR_003137.2	n.64_65insT		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNU4-2	ENST00000365668.1	n.64_65insT		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant with known effect. Systemic disruption to to 5' splice site usage was observed in RNA-sequencing data from five individuals with RNU4-2 variants, three of whom harboured the n.64_65insT variant (PMID: 38991538). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0600 - Variant is located in the defined critical and highly constrained 18bp region in RNU4-2 (PMID: 38991538). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic de novo variant that has been observed in individuals with neurodevelopmental syndrome (PMID: 38991538). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Nov 12, 2024	See PMID: 38991538. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 21, 2024	Criteria applied: PM2_MOD,PS2_VSTR,PS4_STR -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 03, 2024	- -

RNU4-2-related condition Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

May 31, 2024

functional studies, see Chen et al.. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

RNU4-2: PS2:Very Strong, PM2, PS4:Moderate -

RNU4-2-associated neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

Institute of Human Genetics, University of Leipzig Medical Center

Apr 10, 2024

This variant was identified as de novo (maternity and paternity confirmed). Criteria applied: PS2_VSTR, PS4_VSTR -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-120729642;