rs587777329

Positions:

• chr3-9475617-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001080517.3(SETD5):​c.3856del​(p.Ser1286LeufsTer84) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETD5 NM_001080517.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 2.38

Genes affected

SETD5 (HGNC:25566): (SET domain containing 5) This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.109 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-9475617-CT-C is Pathogenic according to our data. Variant chr3-9475617-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127106.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=3, Uncertain_significance=1}. Variant chr3-9475617-CT-C is described in Lovd as [Pathogenic]. Variant chr3-9475617-CT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD5	NM_001080517.3	c.3856del	p.Ser1286LeufsTer84	frameshift_variant	23/23	ENST00000402198.7	NP_001073986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD5	ENST00000402198.7	c.3856del	p.Ser1286LeufsTer84	frameshift_variant	23/23	5	NM_001080517.3	ENSP00000385852	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 157 amino acids are lost and replaced with 83 incorrect amino acids; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24680889) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 12, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SETD5 protein in which other variant(s) (p.Ser1286Leufs*37) have been determined to be pathogenic (PMID: 28549204; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 127106). This premature translational stop signal has been observed in individual(s) with severe intellectual disability (PMID: 24680889). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1286Leufs*84) in the SETD5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 157 amino acid(s) of the SETD5 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 03, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.3562del;p.(Ser1188Leufs*84) is a null frameshift variant in the SETD5 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_strong. This variant is not present in population databases (rs587777329, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777329; hg19: chr3-9517301;