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

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_001080517.3(SETD5):c.2347-7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000908, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SETD5 NM_001080517.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007142
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 0 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000908 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

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

SETD5 NM_001080517.3

MANE Select

HGVSc / HGVSpc.2347-7A>T

Exon rankIntron 16 of 22

splice_regionintron

Prot: NP_001073986.1UniProt: Q9C0A6-1

SETD5 NM_001437635.1

HGVSc / HGVSpc.2404-7A>T

Exon rankIntron 16 of 23

splice_regionintron

Prot: NP_001424564.1

SETD5 NM_001437633.1

HGVSc / HGVSpc.2443-7A>T

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>T	splice_regionintron	Intron 16 of 22	Prot: ENSP00000385852.2 UniProt:
	SETD5 ENST00000493918.5	TSL:1	n.2511-7A>T	splice_regionintron	Intron 12 of 18	Prot:
	SETD5 ENST00000682536.1		c.2443-7A>T	splice_regionintron	Intron 17 of 23	Prot: ENSP00000507956.1 UniProt:

SETD5 ENST00000402198.7

TSL:5MANE Select

HGVSc / HGVSpc.2347-7A>T

Exon rankIntron 16 of 22

splice_regionintron

Prot: ENSP00000385852.2UniProt: Q9C0A6-1

SETD5 ENST00000493918.5

TSL:1

HGVSc / HGVSpn.2511-7A>T

Exon rankIntron 12 of 18

splice_regionintron

Prot:

SETD5 ENST00000682536.1

HGVSc / HGVSpc.2443-7A>T

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 Warning	AF: 7.02e-7	AC:1	Hom:0	AN:1424668	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.4
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.89
DANN	Benign	0.57
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
PhyloP100	Benign	-0.40

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.012
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 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