rs4785714

Variant names:

• chr16-89731996-C-A
• rs4785714
• NM_001113525.2:c.1170-1306C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89731996-C-A
• chr16-89731996-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001113525.2(ZNF276):​c.1170-1306C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,192 control chromosomes in the GnomAD database, including 9,594 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9590 hom., cov: 33)
  • Exomes 𝑓: 0.50 (4 hom.)
• Consequence: ZNF276 NM_001113525.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.942
• Publications: 14 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: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF276	NM_001113525.2	MANE Select	c.1170-1306C>A		intron	N/A	NP_001106997.1
	ZNF276	NM_152287.4		c.945-1306C>A		intron	N/A	NP_689500.2
	ZNF276	NR_110122.2		n.1240-1306C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.1170-1306C>A		intron	N/A	ENSP00000415836.2
	ZNF276	ENST00000289816.9	TSL:1	c.945-1306C>A		intron	N/A	ENSP00000289816.5
	ZNF276	ENST00000564004.5	TSL:2	n.471C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50568 AN: 152046 Hom.: 9590 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.500 AC: 14 AN: 28 Hom.: 4 Cov.: 0 AF XY: 0.389 AC XY: 7 AN XY: 18

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.455 AC: 10 AN: 22

Other (OTH) AF: 0.500 AC: 2 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0504396), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.332 AC: 50588 AN: 152164 Hom.: 9590 Cov.: 33 AF XY: 0.326 AC XY: 24224 AN XY: 74410

African (AFR) AF: 0.202 AC: 8391 AN: 41508

American (AMR) AF: 0.326 AC: 4980 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1665 AN: 3466

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5186

South Asian (SAS) AF: 0.199 AC: 962 AN: 4828

European-Finnish (FIN) AF: 0.377 AC: 3996 AN: 10590

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29151 AN: 67986

Other (OTH) AF: 0.364 AC: 769 AN: 2112

Alfa AF: 0.370 Hom.: 17002

Bravo AF: 0.321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.8
DANN	Benign	0.73
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4785714; hg19: chr16-89798404;