rs138447102

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_021008.4(DEAF1):​c.1186G>A​(p.Gly396Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

DEAF1
NM_021008.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.42
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.009804159).
BP6
Variant 11-678763-C-T is Benign according to our data. Variant chr11-678763-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr11-678763-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000861 (131/152172) while in subpopulation NFE AF= 0.0014 (95/68030). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DEAF1NM_021008.4 linkuse as main transcriptc.1186G>A p.Gly396Ser missense_variant 9/12 ENST00000382409.4 NP_066288.2 O75398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DEAF1ENST00000382409.4 linkuse as main transcriptc.1186G>A p.Gly396Ser missense_variant 9/121 NM_021008.4 ENSP00000371846.3 O75398-1

Frequencies

GnomAD3 genomes
AF:
0.000861
AC:
131
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.0186
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00140
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000732
AC:
184
AN:
251454
Hom.:
0
AF XY:
0.000736
AC XY:
100
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000607
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00138
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.00120
AC:
1754
AN:
1461848
Hom.:
1
Cov.:
31
AF XY:
0.00120
AC XY:
875
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000738
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000936
Gnomad4 NFE exome
AF:
0.00149
Gnomad4 OTH exome
AF:
0.000828
GnomAD4 genome
AF:
0.000861
AC:
131
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.000794
AC XY:
59
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000314
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00140
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.00133
Hom.:
0
Bravo
AF:
0.000801
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.000684
AC:
83
EpiCase
AF:
0.00125
EpiControl
AF:
0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsSep 11, 2017- -
Intellectual disability-epilepsy-extrapyramidal syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterJun 18, 2020- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 11, 2022This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
DEAF1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 17, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
18
DANN
Benign
0.90
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.086
N
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.0098
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.14
N
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.35
N
REVEL
Benign
0.033
Sift
Benign
0.19
T
Sift4G
Benign
0.70
T
Polyphen
0.35
B
Vest4
0.17
MVP
0.58
MPC
0.62
ClinPred
0.0052
T
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.031
gMVP
0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138447102; hg19: chr11-678763; API