16-89727323-C-T

Position:

• chr16-89727323-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001113525.2(ZNF276):​c.1051C>T​(p.Arg351Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00858 in 1,613,734 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0063 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (82 hom.)
• Consequence: ZNF276 NM_001113525.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.33

Genes affected

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ZNF276 (HGNC:):

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058114827).
• BP6: Variant 16-89727323-C-T is Benign according to our data. Variant chr16-89727323-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2647133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF276	NM_001113525.2	c.1051C>T	p.Arg351Trp	missense_variant	5/11	ENST00000443381.7	NP_001106997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF276	ENST00000443381.7	c.1051C>T	p.Arg351Trp	missense_variant	5/11	1	NM_001113525.2	ENSP00000415836.2

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 961 AN: 152006 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00748

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00535 AC: 1345 AN: 251440 Hom.: 4 AF XY: 0.00538 AC XY: 731 AN XY: 135900

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00846

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00881 AC: 12881 AN: 1461610 Hom.: 82 Cov.: 31 AF XY: 0.00851 AC XY: 6191 AN XY: 727098

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00495

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00934

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152124 Hom.: 3 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74348

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00747

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00473

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00855 Hom.: 17

Bravo AF: 0.00594

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00523 AC: 635

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00782

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

ZNF276: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		1.0	.;D
Vest4		0.72
MVP		0.13
MPC		0.11
ClinPred		0.021	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.30

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: rs17719249; hg19: chr16-89793731; COSMIC: COSV104390216; COSMIC: COSV104390216;