Genetic Variant DPF2:p.Arg350His (chr11-65348881-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_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 (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPF2
NM_006268.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 10.0

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]

DPF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a zinc_finger_region PHD-type 2 (size 50) in uniprot entity REQU_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_006268.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the DPF2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 2.8982 (below the threshold of 3.09). Trascript score misZ: 3.3532 (above the threshold of 3.09). GenCC associations: The gene is linked to Coffin-Siris syndrome 7, Coffin-Siris syndrome.

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 rank	MANE	Protein	UniProt
DPF2	NM_006268.5 link	c.1049G>A	p.Arg350His	missense_variant	Exon 10 of 11	ENST00000528416.6	NP_006259.1	Q92785-1A0A024R582
DPF2	NM_001330308.2 link	c.1091G>A	p.Arg364His	missense_variant	Exon 11 of 12		NP_001317237.1	J3KMZ8
DPF2	XM_017018101.3 link	c.1031G>A	p.Arg344His	missense_variant	Exon 11 of 12		XP_016873590.1
DPF2	XR_007062491.1 link	n.1005G>A		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPF2	ENST00000528416.6 link	c.1049G>A	p.Arg350His	missense_variant	Exon 10 of 11	1	NM_006268.5	ENSP00000436901.1		Q92785-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Feb 07, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Coffin-Siris syndrome 7

Pathogenic:1

Jun 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

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

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Pathogenic

0.93

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over