rs191404781

Positions:

• chr16-89739087-G-A
• chr16-89739087-G-C
• chr16-89739087-G-T

Variant summary

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

The NM_001113525.2(ZNF276):​c.*841G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: ZNF276 NM_001113525.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: -1.42

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]

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=0.0069179535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF276	NM_001113525.2	c.*841G>A		3_prime_UTR_variant	11/11	ENST00000443381.7	NP_001106997.1
FANCA	NM_000135.4	c.4167+46C>T		intron_variant		ENST00000389301.8	NP_000126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF276	ENST00000443381.7	c.*841G>A		3_prime_UTR_variant	11/11	1	NM_001113525.2	ENSP00000415836	P2
FANCA	ENST00000389301.8	c.4167+46C>T		intron_variant		1	NM_000135.4	ENSP00000373952	P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000993 AC: 249 AN: 250828 Hom.: 0 AF XY: 0.000922 AC XY: 125 AN XY: 135634

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00105 AC: 1529 AN: 1461510 Hom.: 1 Cov.: 35 AF XY: 0.00102 AC XY: 741 AN XY: 727026

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.000900

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74488

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000526 Hom.: 0

Bravo AF: 0.000722

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Feb 28, 2020

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.0
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0069	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.1	N
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0040	D
MVP		0.82
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs191404781; hg19: chr16-89805495; COSMIC: COSV57068604; COSMIC: COSV57068604;