NM_014712.3:c.2209C>A

Variant names:

• chr16-30966090-C-A
• rs869312831
• NM_014712.3:c.2209C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014712.3(SETD1A):​c.2209C>A​(p.Gln737Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SETD1A NM_014712.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 0 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37393847).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	NM_014712.3	MANE Select	c.2209C>A	p.Gln737Lys	missense	Exon 8 of 19	NP_055527.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	ENST00000262519.14	TSL:1 MANE Select	c.2209C>A	p.Gln737Lys	missense	Exon 8 of 19	ENSP00000262519.8
	SETD1A	ENST00000684162.1		c.2209C>A	p.Gln737Lys	missense	Exon 8 of 19	ENSP00000507683.1
	SETD1A	ENST00000710314.1		c.2209C>A	p.Gln737Lys	missense	Exon 8 of 19	ENSP00000518195.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439642 Hom.: 0 Cov.: 38 AF XY: 0.00000140 AC XY: 1 AN XY: 713450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33094

American (AMR) AF: 0.00 AC: 0 AN: 43170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24530

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 83338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099474

Other (OTH) AF: 0.00 AC: 0 AN: 59360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		0.82	P
Vest4		0.54
MutPred		0.34		Gain of methylation at Q737 (P = 0.002)
MVP		0.75
MPC		0.44
ClinPred		0.63	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.50

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

Other links and lift over

dbSNP: rs869312831; hg19: chr16-30977411;