NM_021008.4:c.288A>G

Variant names:

• chr11-694760-T-C
• NM_021008.4:c.288A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021008.4(DEAF1):​c.288A>G​(p.Ala96Ala) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEAF1 NM_021008.4 splice_region, synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70
• 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]

EPS8L2 (HGNC:21296): (EPS8 signaling adaptor L2) This gene encodes a member of the EPS8 gene family. The encoded protein, like other members of the family, is thought to link growth factor stimulation to actin organization, generating functional redundancy in the pathways that regulate actin cytoskeletal remodeling. [provided by RefSeq, Dec 2008]

EPS8L2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 106

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.288A>G	p.Ala96Ala	splice_region synonymous	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440885.1		c.-309A>G		splice_region	Exon 1 of 11	NP_001427814.1
	DEAF1	NM_001440883.1		c.288A>G	p.Ala96Ala	splice_region synonymous	Exon 1 of 11	NP_001427812.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.288A>G	p.Ala96Ala	splice_region synonymous	Exon 1 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000882097.1		c.288A>G	p.Ala96Ala	splice_region synonymous	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000685854.1		c.84A>G	p.Ala28Ala	splice_region synonymous	Exon 1 of 14	ENSP00000508801.1	A0A8I5KQY1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1148434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 553748

African (AFR) AF: 0.00 AC: 0 AN: 23056

American (AMR) AF: 0.00 AC: 0 AN: 8786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15128

East Asian (EAS) AF: 0.00 AC: 0 AN: 26292

South Asian (SAS) AF: 0.00 AC: 0 AN: 38330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3158

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 961754

Other (OTH) AF: 0.00 AC: 0 AN: 46444

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.90
PhyloP100		3.7
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.71		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-694760;