NM_001080517.3:c.2347-7A>G

Variant names:

• chr3-9453732-A-G
• rs886041593
• NM_001080517.3:c.2347-7A>G

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM2PP3_ModeratePP5_Strong

The NM_001080517.3(SETD5):c.2347-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000330285: Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay) (Kobayashi et al., 2016)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD5 NM_001080517.3 splice_region, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.397
• Publications: 1 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 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000330285: Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay) (Kobayashi et al., 2016); SCV000741431: One functional study demonstrated that this alteration results in abnormal splicing (Kobayashi, 2016).; SCV001761129: Analysis of cDNA obtained from a patient derived lymphoblastoid cell line showed that this splice region variant introduces premature stop codon and the mutant mRNA is subjected to nonsense mediated decay [PMID: 26482601].; SCV003915915: Published functional studies demonstrate a damaging effect (insertion of a 6-bp intronic sequence causing a premature stop codon and nonsense-mediated mRNA decay). Kobayashi Y et al., 2016, Powis Z et al., 2018).; SCV005086051: Published functional studies using RT-PCR and next generation sequencing on a patient-derived lymphoblastoid cell line identified a 6bp insertion within the intronic sequence, introducing a premature stop codon and resulting in subsequent nonsense-mediated mRNA decay (PMID: 26482601).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (11/11 total P/LP).

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.2347-7A>G	splice_regionintron	Intron 16 of 22	Prot: NP_001073986.1 UniProt:
	SETD5 NM_001437635.1		c.2404-7A>G	splice_regionintron	Intron 16 of 23	Prot: NP_001424564.1
	SETD5 NM_001437633.1		c.2443-7A>G	splice_regionintron	Intron 17 of 23	Prot: NP_001424562.1 UniProt:

SETD5 NM_001080517.3

MANE Select

HGVSc / HGVSpc.2347-7A>G

Exon rankIntron 16 of 22

splice_regionintron

Prot: NP_001073986.1UniProt: Q9C0A6-1

SETD5 NM_001437635.1

HGVSc / HGVSpc.2404-7A>G

Exon rankIntron 16 of 23

splice_regionintron

Prot: NP_001424564.1

SETD5 NM_001437633.1

HGVSc / HGVSpc.2443-7A>G

Exon rankIntron 17 of 23

splice_regionintron

Prot: NP_001424562.1UniProt: A0A804HKJ9

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SETD5 ENST00000402198.7	TSL:5MANE Select	c.2347-7A>G	splice_regionintron	Intron 16 of 22	Prot: ENSP00000385852.2 UniProt:
	SETD5 ENST00000493918.5	TSL:1	n.2511-7A>G	splice_regionintron	Intron 12 of 18	Prot:
	SETD5 ENST00000682536.1		c.2443-7A>G	splice_regionintron	Intron 17 of 23	Prot: ENSP00000507956.1 UniProt:

SETD5 ENST00000402198.7

TSL:5MANE Select

HGVSc / HGVSpc.2347-7A>G

Exon rankIntron 16 of 22

splice_regionintron

Prot: ENSP00000385852.2UniProt: Q9C0A6-1

SETD5 ENST00000493918.5

TSL:1

HGVSc / HGVSpn.2511-7A>G

Exon rankIntron 12 of 18

splice_regionintron

Prot:

SETD5 ENST00000682536.1

HGVSc / HGVSpc.2443-7A>G

Exon rankIntron 17 of 23

splice_regionintron

Prot: ENSP00000507956.1UniProt: 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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (5)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	See cases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
BayesDel_noAF	Benign	-0.75
CADD	Benign	22
DANN	Benign	0.59
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
Mutation Taster	N/A	8/92	disease causing (ClinVar)
PhyloP100	Benign	-0.40
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
DS_AG_spliceai	Pathogenic	1.0	Position offset: 1
DS_AL_spliceai	Pathogenic	0.65	Position offset: 7
Pangolin (max)	Pathogenic	0.89
Pangolin gain	Pathogenic	0.89	Position offset: 1
Pangolin loss	Pathogenic	0.85	Position offset: 7
SpliceAI score (max)	Pathogenic	1.0	Details are displayed if max score is > 0.2

Showing 8 of 8 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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs886041593;

hg19: chr3-9495416;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar