NM_021008.4:c.1123A>G

Variant names:

• chr11-679691-T-C
• rs1135401947
• NM_021008.4:c.1123A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021008.4(DEAF1):​c.1123A>G​(p.Thr375Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T375T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

Genes affected

DEAF1 (HGNC:14677): (DEAF1 transcription factor) This gene encodes a zinc finger domain-containing protein that functions as a regulator of transcription. The encoded proteins binds to its own promoter as well as to that of several target genes. Activity of this protein is important in the regulation of embryonic development. Mutations in this gene have been found in individuals with autosomal dominant cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DEAF1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability-epilepsy-extrapyramidal syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: SD Classification: STRONG Submitted by: Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19402504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021008.4. 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
	DEAF1	NM_021008.4	MANE Select	c.1123A>G	p.Thr375Ala	missense	Exon 8 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.1123A>G	p.Thr375Ala	missense	Exon 8 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.1123A>G	p.Thr375Ala	missense	Exon 8 of 11	NP_001427813.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.1123A>G	p.Thr375Ala	missense	Exon 8 of 12	ENSP00000371846.3
	DEAF1	ENST00000527170.5	TSL:1	n.484A>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000431563.1
	DEAF1	ENST00000882097.1		c.1249A>G	p.Thr417Ala	missense	Exon 9 of 13	ENSP00000552156.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459738 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726316

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.63	N
PhyloP100		2.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.034
Sift	Benign	0.091	T
Sift4G	Benign	0.39	T
Polyphen		0.24	B
Vest4		0.26
MutPred		0.17		Gain of helix (P = 0.005)
MVP		0.66
MPC		0.61
ClinPred		0.33	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.44
Mutation Taster		=75/25	polymorphism

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: rs1135401947; hg19: chr11-679691;