chr11-694949-T-G

Variant names:

• chr11-694949-T-G
• rs895976430
• NM_021008.4:c.99A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_021008.4(DEAF1):​c.99A>C​(p.Ala33Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,140,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DEAF1 NM_021008.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.53
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-694949-T-G is Benign according to our data. Variant chr11-694949-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 434929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.

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.99A>C	p.Ala33Ala	synonymous	Exon 1 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.99A>C	p.Ala33Ala	synonymous	Exon 1 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.99A>C	p.Ala33Ala	synonymous	Exon 1 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.99A>C	p.Ala33Ala	synonymous	Exon 1 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000882097.1		c.99A>C	p.Ala33Ala	synonymous	Exon 1 of 13	ENSP00000552156.1
	DEAF1	ENST00000917805.1		c.99A>C	p.Ala33Ala	synonymous	Exon 1 of 12	ENSP00000587864.1

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 21 AN: 146382 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000242

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000686 AC: 3 AN: 43716 AF XY: 0.0000727

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000301 AC: 299 AN: 993906 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 149 AN XY: 480924

African (AFR) AF: 0.000480 AC: 9 AN: 18752

American (AMR) AF: 0.000516 AC: 4 AN: 7756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12300

East Asian (EAS) AF: 0.0000640 AC: 1 AN: 15632

South Asian (SAS) AF: 0.00 AC: 0 AN: 29624

European-Finnish (FIN) AF: 0.000430 AC: 5 AN: 11634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2418

European-Non Finnish (NFE) AF: 0.000321 AC: 276 AN: 859512

Other (OTH) AF: 0.000110 AC: 4 AN: 36278

GnomAD4 genome AF: 0.000143 AC: 21 AN: 146512 Hom.: 0 Cov.: 32 AF XY: 0.000126 AC XY: 9 AN XY: 71478

African (AFR) AF: 0.0000986 AC: 4 AN: 40560

American (AMR) AF: 0.0000678 AC: 1 AN: 14744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4614

South Asian (SAS) AF: 0.00 AC: 0 AN: 4232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000242 AC: 16 AN: 66170

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.000253 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		-1.5
PromoterAI		0.060	Neutral
Mutation Taster		=99/1	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: rs895976430; hg19: chr11-694949; COSMIC: COSV58605629; COSMIC: COSV58605629;