NM_014712.3:c.1938C>G

Variant names:

• chr16-30965819-C-G
• rs770913157
• NM_014712.3:c.1938C>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014712.3(SETD1A):​c.1938C>G​(p.Tyr646*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: SETD1A NM_014712.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.695

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 16-30965819-C-G is Pathogenic according to our data. Variant chr16-30965819-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 224654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1A	NM_014712.3	c.1938C>G	p.Tyr646*	stop_gained	Exon 8 of 19	ENST00000262519.14	NP_055527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1A	ENST00000262519.14	c.1938C>G	p.Tyr646*	stop_gained	Exon 8 of 19	1	NM_014712.3	ENSP00000262519.8
SETD1A	ENST00000684162.1	c.1938C>G	p.Tyr646*	stop_gained	Exon 8 of 19			ENSP00000507683.1
SETD1A	ENST00000710314.1	c.1938C>G	p.Tyr646*	stop_gained	Exon 8 of 19			ENSP00000518195.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schizophrenia Pathogenic:1

Mar 14, 2016

SNPedia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:1

May 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SETD1A are known to be pathogenic (PMID: 32346159). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with SETD1A-related disease (PMID: 26974950, Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 16:30977140_C/G in the literature. ClinVar contains an entry for this variant (Variation ID: 224654). This sequence change creates a premature translational stop signal (p.Tyr646*) in the SETD1A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.59
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs770913157; hg19: chr16-30977140;