rs1555031372

chr11-65345981-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_006268.5(DPF2):c.827G>T(p.Cys276Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPF2 NM_006268.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a zinc_finger_region PHD-type 1 (size 60) in uniprot entity REQU_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006268.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DPF2
• PP5: Variant 11-65345981-G-T is Pathogenic according to our data. Variant chr11-65345981-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 438643.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-65345981-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPF2	NM_006268.5	c.827G>T	p.Cys276Phe	missense_variant	8/11	ENST00000528416.6
DPF2	NM_001330308.2	c.869G>T	p.Cys290Phe	missense_variant	9/12
DPF2	XM_017018101.3	c.809G>T	p.Cys270Phe	missense_variant	9/12
DPF2	XR_007062491.1	n.783G>T		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPF2	ENST00000528416.6	c.827G>T	p.Cys276Phe	missense_variant	8/11	1	NM_006268.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Sep 14, 2017

De novo missense variant in DPF2 identified in a male patient with developmental delay, speech impairment, intellectual disability, short stature, behavioral anomalies, brachydactyly of the fifth finger and hypoplasia of the fifth toenail. -

Coffin-Siris syndrome 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.27	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.53
Sift	Benign	0.38	T
Sift4G	Uncertain	0.038	D
MutPred		0.32		Gain of disorder (P = 0.0269);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555031372; hg19: chr11-65113452;