rs34114147

Variant names:

• chr11-644614-G-C
• rs34114147
• NM_021008.4:c.1634C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021008.4(DEAF1):​c.1634C>G​(p.Ala545Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,612,816 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A545P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (71 hom.)
• Consequence: DEAF1 NM_021008.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.14
• Publications: 11 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]

DEAF1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability-epilepsy-extrapyramidal syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: SD Classification: STRONG Submitted by: Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045463145).
• BP6: Variant 11-644614-G-C is Benign according to our data. Variant chr11-644614-G-C is described in ClinVar as Benign. ClinVar VariationId is 434924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00672 (1024/152278) while in subpopulation AMR AF = 0.0127 (195/15304). AF 95% confidence interval is 0.0113. There are 13 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	NM_021008.4	MANE Select	c.1634C>G	p.Ala545Gly	missense	Exon 12 of 12	NP_066288.2
	DEAF1	NM_001440883.1		c.1544C>G	p.Ala515Gly	missense	Exon 11 of 11	NP_001427812.1
	DEAF1	NM_001440884.1		c.1505C>G	p.Ala502Gly	missense	Exon 11 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.1634C>G	p.Ala545Gly	missense	Exon 12 of 12	ENSP00000371846.3
	DEAF1	ENST00000527170.5	TSL:1	n.*194C>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000431563.1
	DEAF1	ENST00000527170.5	TSL:1	n.*194C>G		3_prime_UTR	Exon 10 of 10	ENSP00000431563.1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152160 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00662 AC: 1650 AN: 249184 AF XY: 0.00627

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00836 AC: 12212 AN: 1460538 Hom.: 71 Cov.: 31 AF XY: 0.00798 AC XY: 5799 AN XY: 726594

African (AFR) AF: 0.00146 AC: 49 AN: 33478

American (AMR) AF: 0.0113 AC: 504 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86182

European-Finnish (FIN) AF: 0.00627 AC: 328 AN: 52346

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00966 AC: 10740 AN: 1111878

Other (OTH) AF: 0.00747 AC: 451 AN: 60378

GnomAD4 genome AF: 0.00672 AC: 1024 AN: 152278 Hom.: 13 Cov.: 32 AF XY: 0.00649 AC XY: 483 AN XY: 74464

African (AFR) AF: 0.00212 AC: 88 AN: 41568

American (AMR) AF: 0.0127 AC: 195 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 68006

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00751 Hom.: 4

Bravo AF: 0.00744

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00597 AC: 725

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.053
MVP		0.77
MPC		0.68
ClinPred		0.0028	T
GERP RS		3.3
Varity_R		0.047
gMVP		0.14
Mutation Taster		=90/10	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: rs34114147; hg19: chr11-644614; COSMIC: COSV99448606; COSMIC: COSV99448606;