rs1554944271

Positions:

• chr11-686925-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_021008.4(DEAF1):​c.737G>C​(p.Arg246Thr) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_021008.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-686925-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2809336.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 11-686925-C-G is Pathogenic according to our data. Variant chr11-686925-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEAF1	NM_021008.4	c.737G>C	p.Arg246Thr	missense_variant	5/12	ENST00000382409.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEAF1	ENST00000382409.4	c.737G>C	p.Arg246Thr	missense_variant	5/12	1	NM_021008.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 24 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 25, 2021	The DEAF1 c.737G>C variant is a single nucleotide change in exon 5 of the DEAF1 gene, which is predicted to change the amino acid arginine at position 246 in the protein to threonine. This variant is de novo in this individual (PS2) and has been reported in at least one other individual with autosomal dominant mental retardation 24 (PS4_supporting). Functional studies have shown reduced transcriptional repression activity and decreased binding to dsDNA compared with wild type (PS3_moderate; PMID:28940898). This variant has not been reported in dbSNP and is absent from population databases (PM2). This variant has been reported in ClinVar as likely pathogenic for mental retardation by another diagnostic laboratory (ClinVar Variation ID: 437396), and in HMGD as damaging for mental retardation 24 (CM171837). Computational predictions support a deleterious effect on the gene or gene product (PP3). The DEAF1 c.737G>C variant is classified as PATHOGENIC (PM2, PP3, PS2, PS3_moderate, PS4_supporting) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 02, 2015	This missense variant has been observed once in our laboratory de novo in an 8-year-old female with intellectual disability, autism spectrum disorder, partial seizures, slight prenatal growth retardation, aggressive behavior, self-injurious behavior, mild low-frequency hearing loss, unilateral ear tag, congenital hip dislocation, slightly low cerebellar tonils, abnormal EEG. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.55		Loss of MoRF binding (P = 0.025);
MVP		0.84
MPC		1.9
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.92

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: rs1554944271; hg19: chr11-686925;