11-65348869-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_006268.5(DPF2):​c.1037A>G​(p.Asp346Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D346N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

DPF2
NM_006268.5 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
DPF2 (HGNC:9964): (double PHD fingers 2) The protein encoded by this gene is a member of the d4 domain family, characterized by a zinc finger-like structural motif. This protein functions as a transcription factor which is necessary for the apoptotic response following deprivation of survival factors. It likely serves a regulatory role in rapid hematopoietic cell growth and turnover. This gene is considered a candidate gene for multiple endocrine neoplasia type I, an inherited cancer syndrome involving multiple parathyroid, enteropancreatic, and pituitary tumors. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_006268.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-65348868-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1200174.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DPF2. . Gene score misZ 2.8982 (greater than the threshold 3.09). Trascript score misZ 3.3532 (greater than threshold 3.09). GenCC has associacion of gene with Coffin-Siris syndrome 7, Coffin-Siris syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
Variant 11-65348869-A-G is Pathogenic according to our data. Variant chr11-65348869-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 545685.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-65348869-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DPF2NM_006268.5 linkuse as main transcriptc.1037A>G p.Asp346Gly missense_variant 10/11 ENST00000528416.6
DPF2NM_001330308.2 linkuse as main transcriptc.1079A>G p.Asp360Gly missense_variant 11/12
DPF2XM_017018101.3 linkuse as main transcriptc.1019A>G p.Asp340Gly missense_variant 11/12
DPF2XR_007062491.1 linkuse as main transcriptn.993A>G non_coding_transcript_exon_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DPF2ENST00000528416.6 linkuse as main transcriptc.1037A>G p.Asp346Gly missense_variant 10/111 NM_006268.5 P1Q92785-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Coffin-Siris syndrome 7 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Lab, CHRU Brest-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 28, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.;T;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.1
D;D;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0040
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.97
MutPred
0.82
Loss of stability (P = 0.0077);.;.;.;
MVP
0.96
MPC
3.2
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.72
gMVP
0.91

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: rs1555032044; hg19: chr11-65116340; COSMIC: COSV52888454; COSMIC: COSV52888454; API