NM_021008.4:c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC

Variant names:

• chr11-694952-C-CGCGGCCGCGGCCGCCGCCGCCACA
• rs752994574
• NM_021008.4:c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_021008.4(DEAF1):​c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC​(p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 149,098 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A32A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DEAF1 NM_021008.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• 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: PanelApp Australia, 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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021008.4.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	NM_021008.4	MANE Select	c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 11	NP_001427813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000371846.3
	DEAF1	ENST00000882097.1		c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000917805.1		c.72_95dupTGTGGCGGCGGCGGCCGCGGCCGC	p.Ala32_Ala33insValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000587864.1

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000655 AC: 7 AN: 1069136 Hom.: 0 Cov.: 32 AF XY: 0.00000581 AC XY: 3 AN XY: 516198

African (AFR) AF: 0.00 AC: 0 AN: 21048

American (AMR) AF: 0.00 AC: 0 AN: 8750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13950

East Asian (EAS) AF: 0.00 AC: 0 AN: 21026

South Asian (SAS) AF: 0.00 AC: 0 AN: 27746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2774

European-Non Finnish (NFE) AF: 0.00000766 AC: 7 AN: 913862

Other (OTH) AF: 0.00 AC: 0 AN: 40958

GnomAD4 genome AF: 0.0000402 AC: 6 AN: 149098 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 3 AN XY: 72708

African (AFR) AF: 0.0000487 AC: 2 AN: 41096

American (AMR) AF: 0.00 AC: 0 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66684

Other (OTH) AF: 0.00 AC: 0 AN: 2054

ClinVar

ClinVar submissions as Germline

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
PhyloP100		2.8
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs752994574; hg19: chr11-694952;