rs587777329

Variant names:

• chr3-9475617-CT-C
• rs587777329
• NM_001080517.3:c.3856delT

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2_SupportingPP5_Strong

The NM_001080517.3(SETD5):c.3856delT (p.Ser1286LeufsTer84) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. The variant allele was found at a cumulative frequency of 0.00000205 (AC=3) in the gnomAD database across 1,461,712 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETD5 NM_001080517.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.38
• Publications: 6 publications found

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]

SETD5 Gene-Disease associations (from GenCC):

• intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 23 of 23) at amino acid 1286 of 1442; NMD not predicted. 8 pathogenic variants downstream support preserved loss-of-function impact. A new stop codon is introduced in the shifted frame, truncating the protein to ~1368 amino acids (74 amino acids lost).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000116 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001080517.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	NM_001080517.3	MANE Select	c.3856delT	p.Ser1286LeufsTer84	frameshift	Exon 23 of 23	NP_001073986.1	Q9C0A6-1
	SETD5	NM_001437635.1		c.3970delT	p.Ser1324LeufsTer84	frameshift	Exon 24 of 24	NP_001424564.1
	SETD5	NM_001437633.1		c.3952delT	p.Ser1318LeufsTer84	frameshift	Exon 24 of 24	NP_001424562.1	A0A804HKJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD5	ENST00000402198.7	TSL:5 MANE Select	c.3856delT	p.Ser1286LeufsTer84	frameshift	Exon 23 of 23	ENSP00000385852.2	Q9C0A6-1
	SETD5	ENST00000493918.5	TSL:1	n.4020delT		non_coding_transcript_exon	Exon 19 of 19
	SETD5	ENST00000682536.1		c.3952delT	p.Ser1318LeufsTer84	frameshift	Exon 24 of 24	ENSP00000507956.1	A0A804HKJ9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249238	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461712	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability, autosomal dominant 45 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	1/199	disease causing (ClinVar)
PhyloP100	Benign	2.4

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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: rs587777329;

hg19: chr3-9517301;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar