rs17719249

Variant names:

• chr16-89727323-C-T
• rs17719249
• NM_001113525.2:c.1051C>T

Variant summary

Our verdict is Benign. The variant received -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 (★).

• 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
• Publications: 17 publications found

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]

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]

FANCA Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 2647133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113525.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF276	NM_001113525.2	MANE Select	c.1051C>T	p.Arg351Trp	missense	Exon 5 of 11	NP_001106997.1	Q8N554-1
	ZNF276	NM_152287.4		c.826C>T	p.Arg276Trp	missense	Exon 5 of 11	NP_689500.2
	ZNF276	NR_110122.2		n.1121C>T		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.1051C>T	p.Arg351Trp	missense	Exon 5 of 11	ENSP00000415836.2	Q8N554-1
	ZNF276	ENST00000289816.9	TSL:1	c.826C>T	p.Arg276Trp	missense	Exon 5 of 11	ENSP00000289816.5	Q8N554-2
	ZNF276	ENST00000950694.1		c.1051C>T	p.Arg351Trp	missense	Exon 6 of 12	ENSP00000620753.1

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

GnomAD2 exomes AF: 0.00535 AC: 1345 AN: 251440 AF XY: 0.00538

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 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

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 186 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86252

European-Finnish (FIN) AF: 0.00495 AC: 264 AN: 53372

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0104 AC: 11586 AN: 1111800

Other (OTH) AF: 0.00934 AC: 564 AN: 60384

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

African (AFR) AF: 0.00219 AC: 91 AN: 41498

American (AMR) AF: 0.00747 AC: 114 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00473 AC: 50 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 68018

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00800 Hom.: 20

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.045	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
Mutation Taster		=46/54	disease causing

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

Other links and lift over

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