chr11-65340429-A-G

Position:

• chr11-65340429-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_006268.5(DPF2):​c.77A>G​(p.Asn26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DPF2 NM_006268.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.60

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_benign. Variant got -5 ACMG points.

• 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). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. GenCC has associacion of the gene with Coffin-Siris syndrome 7, Coffin-Siris syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08024767).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPF2	NM_006268.5	c.77A>G	p.Asn26Ser	missense_variant	2/11	ENST00000528416.6	NP_006259.1
DPF2	NM_001330308.2	c.77A>G	p.Asn26Ser	missense_variant	2/12		NP_001317237.1
DPF2	XM_017018101.3	c.17A>G	p.Asn6Ser	missense_variant	2/12		XP_016873590.1
DPF2	XR_007062491.1	n.112A>G		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPF2	ENST00000528416.6	c.77A>G	p.Asn26Ser	missense_variant	2/11	1	NM_006268.5	ENSP00000436901.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251360 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727248

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.77A>G (p.N26S) alteration is located in exon 2 (coding exon 2) of the DPF2 gene. This alteration results from a A to G substitution at nucleotide position 77, causing the asparagine (N) at amino acid position 26 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 26 of the DPF2 protein (p.Asn26Ser). This variant is present in population databases (rs745602444, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DPF2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.045	T;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-1.3	N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.96	T;T;T
Polyphen		0.019	B;.;.
Vest4		0.23
MutPred		0.21		Gain of disorder (P = 0.1399);Gain of disorder (P = 0.1399);Gain of disorder (P = 0.1399);
MVP		0.66
MPC		0.34
ClinPred		0.11	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.046
gMVP		0.11

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: rs745602444; hg19: chr11-65107900;