Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_021008.4(DEAF1):c.72_95delTGTGGCGGCGGCGGCCGCGGCCGC(p.Val25_Ala32del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,218,278 control chromosomes in the GnomAD database, including 62 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A24A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 62 hom. )

Consequence

DEAF1
NM_021008.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.41

Publications

0 publications found

Variant links:

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 links:

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

EPS8L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021008.4.

BP6

Variant 11-694952-CGCGGCCGCGGCCGCCGCCGCCACA-C is Benign according to our data. Variant chr11-694952-CGCGGCCGCGGCCGCCGCCGCCACA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434933.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000674 (721/1069078) while in subpopulation SAS AF = 0.00177 (49/27738). AF 95% confidence interval is 0.00137. There are 62 homozygotes in GnomAdExome4. There are 380 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 62 AD,AR,SD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DEAF1	NM_021008.4	MANE Select	c.72_95delTGTGGCGGCGGCGGCCGCGGCCGC	p.Val25_Ala32del	disruptive_inframe_deletion	Exon 1 of 12	NP_066288.2
DEAF1	NM_001440883.1		c.72_95delTGTGGCGGCGGCGGCCGCGGCCGC	p.Val25_Ala32del	disruptive_inframe_deletion	Exon 1 of 11	NP_001427812.1
DEAF1	NM_001440884.1		c.72_95delTGTGGCGGCGGCGGCCGCGGCCGC	p.Val25_Ala32del	disruptive_inframe_deletion	Exon 1 of 11	NP_001427813.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.72_95delTGTGGCGGCGGCGGCCGCGGCCGC	p.Val25_Ala32del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000371846.3
DEAF1	ENST00000687329.1		n.-133_-110delTGTGGCGGCGGCGGCCGCGGCCGC		non_coding_transcript_exon	Exon 1 of 13	ENSP00000510598.1
DEAF1	ENST00000692634.1		n.-133_-110delTGTGGCGGCGGCGGCCGCGGCCGC		non_coding_transcript_exon	Exon 1 of 10	ENSP00000508859.1

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

149092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000303

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000375

Gnomad OTH

AF:

0.000974

GnomAD2 exomes

AF:

0.00149

AC:

AN:

28254

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.00446

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.00207

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00138

GnomAD4 exome

AF:

0.000674

AC:

721

AN:

1069078

Hom.:

AF XY:

0.000736

AC XY:

380

AN XY:

516174

show subpopulations

African (AFR)

AF:

0.000428

AC:

AN:

21048

American (AMR)

AF:

0.00160

AC:

AN:

8746

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

13946

East Asian (EAS)

AF:

0.000713

AC:

AN:

21026

South Asian (SAS)

AF:

0.00177

AC:

AN:

27738

European-Finnish (FIN)

AF:

0.000894

AC:

AN:

19014

Middle Eastern (MID)

AF:

0.000722

AC:

AN:

2772

European-Non Finnish (NFE)

AF:

0.000631

AC:

577

AN:

913832

Other (OTH)

AF:

0.000513

AC:

AN:

40956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.595

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000369

AC:

AN:

149200

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

AN XY:

72824

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

41210

American (AMR)

AF:

0.000267

AC:

AN:

14996

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3414

East Asian (EAS)

AF:

0.000199

AC:

AN:

5024

South Asian (SAS)

AF:

0.00

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

9908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000375

AC:

AN:

66674

Other (OTH)

AF:

0.000964

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000397

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

DEAF1-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

Mutation Taster

=191/9

polymorphism

(source)

Splicing

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

Publications

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rs752994574

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over