rs869312832

Variant names:

• chr16-30966051-G-GC
• rs869312832
• NM_014712.3:c.2171dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014712.3(SETD1A):​c.2171dupC​(p.Ala725SerfsTer100) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1A NM_014712.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.13
• Publications: 1 publications found

Genes affected

SETD1A (HGNC:29010): (SET domain containing 1A, histone lysine methyltransferase) The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily. [provided by RefSeq, Dec 2016]

SETD1A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder with speech impairment and dysmorphic facies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy, early-onset, with or without developmental delay

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30966051-G-GC is Pathogenic according to our data. Variant chr16-30966051-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 224653.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014712.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	NM_014712.3	MANE Select	c.2171dupC	p.Ala725SerfsTer100	frameshift	Exon 8 of 19	NP_055527.1	O15047

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	ENST00000262519.14	TSL:1 MANE Select	c.2171dupC	p.Ala725SerfsTer100	frameshift	Exon 8 of 19	ENSP00000262519.8	O15047
	SETD1A	ENST00000684162.1		c.2171dupC	p.Ala725SerfsTer100	frameshift	Exon 8 of 19	ENSP00000507683.1	O15047
	SETD1A	ENST00000710314.1		c.2171dupC	p.Ala725SerfsTer100	frameshift	Exon 8 of 19	ENSP00000518195.1	O15047

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Schizophrenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869312832; hg19: chr16-30977372;