Genetic Variant SETD1A:p.Gln737Lys (chr16-30966090-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.79

Publications

0 publications found

Variant links:

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)

SETD1A links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1A	NM_014712.3 link	c.2209C>A	p.Gln737Lys	missense_variant	Exon 8 of 19	ENST00000262519.14	NP_055527.1	O15047

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETD1A	ENST00000262519.14 link	c.2209C>A	p.Gln737Lys	missense_variant	Exon 8 of 19	1	NM_014712.3	ENSP00000262519.8	O15047
SETD1A	ENST00000684162.1 link	c.2209C>A	p.Gln737Lys	missense_variant	Exon 8 of 19			ENSP00000507683.1	O15047
SETD1A	ENST00000710314.1 link	c.2209C>A	p.Gln737Lys	missense_variant	Exon 8 of 19			ENSP00000518195.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439642

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713450

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

43170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24530

East Asian (EAS)

AF:

0.00

AC:

AN:

39430

South Asian (SAS)

AF:

0.00

AC:

AN:

83338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1099474

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.034

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

M_CAP

Benign

0.058

MetaRNN

Benign

0.37

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.4

PhyloP100

5.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.38

Sift

Uncertain

0.0030

Sift4G

Benign

0.17

Polyphen

0.82

Vest4

0.54

MutPred

0.34

Gain of methylation at Q737 (P = 0.002);

MVP

0.75

MPC

0.44

ClinPred

0.63

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over