rs1555032044

Positions:

• chr11-65348869-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000528416.6(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 ENST00000528416.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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]

ACMG classification

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 ENST00000528416.6
• 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	Protein	UniProt
DPF2	NM_006268.5	c.1037A>G	p.Asp346Gly	missense_variant	10/11	ENST00000528416.6	NP_006259.1
DPF2	NM_001330308.2	c.1079A>G	p.Asp360Gly	missense_variant	11/12		NP_001317237.1
DPF2	XM_017018101.3	c.1019A>G	p.Asp340Gly	missense_variant	11/12		XP_016873590.1
DPF2	XR_007062491.1	n.993A>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPF2	ENST00000528416.6	c.1037A>G	p.Asp346Gly	missense_variant	10/11	1	NM_006268.5	ENSP00000436901	P1

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

Submissions by phenotype

Coffin-Siris syndrome 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -

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

Other links and lift over

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