11-7000409-T-C

Position:

• chr11-7000409-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013249.4(ZNF214):​c.1274A>G​(p.Gln425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: ZNF214 NM_013249.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

Genes affected

ZNF214 (HGNC:13006): (zinc finger protein 214) This gene is expressed predominantly in the testis and encodes a zinc finger protein that contains an N-terminal kruppel-associated box A (KRABA) domain and twelve zinc finger domains. This gene is located within one of three regions on chromosome 11p15 associated with Beckwith-Wiedemann syndrome, called Beckwith-Wiedemann syndrome chromosome region-2 (BWSCR2), and is thought to play a role in the etiology of this disease. [provided by RefSeq, Aug 2017]

ZNF215 (HGNC:13007): (zinc finger protein 215) This gene is imprinted in a tissue-specific manner with preferential expression in the testis, and encodes a zinc finger protein that belongs to a family of zinc finger transcription factors. The encoded protein contains an N-terminal SRE-ZBP, Ctfin51, AW-1, and Number 18 (SCAN) domain, a kruppel-associated box A (KRABA) domain, and four C-terminal zinc finger domains. This gene is located within one of three regions on chromosome 11p15 associated with Beckwith-Wiedemann syndrome, called Beckwith-Wiedemann syndrome chromosome region-2 (BWSCR2), and is thought to play a role in the etiology of this disease. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05180511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF214	NM_013249.4	c.1274A>G	p.Gln425Arg	missense_variant	3/3	ENST00000278314.5	NP_037381.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF214	ENST00000278314.5	c.1274A>G	p.Gln425Arg	missense_variant	3/3	1	NM_013249.4	ENSP00000278314.4
ZNF214	ENST00000536068.5	c.1274A>G	p.Gln425Arg	missense_variant	4/4	1		ENSP00000445373.1
ZNF215	ENST00000636606.1	n.*493T>C		non_coding_transcript_exon_variant	7/7	5		ENSP00000490359.1
ZNF215	ENST00000636606.1	n.*493T>C		3_prime_UTR_variant	7/7	5		ENSP00000490359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461334 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726950

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.1274A>G (p.Q425R) alteration is located in exon 3 (coding exon 2) of the ZNF214 gene. This alteration results from a A to G substitution at nucleotide position 1274, causing the glutamine (Q) at amino acid position 425 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.29
DEOGEN2	Benign	0.0019	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.013	B;B
Vest4		0.14
MutPred		0.45		Gain of MoRF binding (P = 0.0165);Gain of MoRF binding (P = 0.0165);
MVP		0.26
MPC		0.040
ClinPred		0.053	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.030

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-7021640;