rs1555032051

chr11-65348881-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_006268.5(DPF2):c.1049G>A(p.Arg350His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DPF2 NM_006268.5 missense
• Clinical Significance: Likely 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 8 ACMG points.

• PM1: In a hotspot region, there are 4 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
• PP2: Missense variant where missense usually causes diseases, DPF2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 11-65348881-G-A is Pathogenic according to our data. Variant chr11-65348881-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545684.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-65348881-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPF2	NM_006268.5	c.1049G>A	p.Arg350His	missense_variant	10/11	ENST00000528416.6
DPF2	NM_001330308.2	c.1091G>A	p.Arg364His	missense_variant	11/12
DPF2	XM_017018101.3	c.1031G>A	p.Arg344His	missense_variant	11/12
DPF2	XR_007062491.1	n.1005G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPF2	ENST00000528416.6	c.1049G>A	p.Arg350His	missense_variant	10/11	1	NM_006268.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2019

- -

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	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D;N;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.048	B;.;.;.
Vest4		0.76
MutPred		0.66		Gain of catalytic residue at D346 (P = 0.1304);.;.;.;
MVP		0.95
MPC		3.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.85

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: rs1555032051; hg19: chr11-65116352; COSMIC: COSV52888106; COSMIC: COSV52888106;