NM_001113525.2:c.*1693A>T

Variant names:

• chr16-89739939-A-T
• rs7195906
• NM_001113525.2:c.*1693A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001113525.2(ZNF276):​c.*1693A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,604,774 control chromosomes in the GnomAD database, including 184,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25010 hom., cov: 33)
  • Exomes 𝑓: 0.45 (159056 hom.)
• Consequence: ZNF276 NM_001113525.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.708
• Publications: 27 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.084).
• BP6: Variant 16-89739939-A-T is Benign according to our data. Variant chr16-89739939-A-T is described in ClinVar as Benign. ClinVar VariationId is 135541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF276	NM_001113525.2	c.*1693A>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000443381.7	NP_001106997.1
FANCA	NM_000135.4	c.3934+55T>A		intron_variant	Intron 39 of 42	ENST00000389301.8	NP_000126.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF276	ENST00000443381.7	c.*1693A>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_001113525.2	ENSP00000415836.2
FANCA	ENST00000389301.8	c.3934+55T>A		intron_variant	Intron 39 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82415 AN: 152026 Hom.: 24964 Cov.: 33

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.474

GnomAD2 exomes AF: 0.523 AC: 130329 AN: 249378 AF XY: 0.509

Gnomad AFR exome AF: 0.775

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.451 AC: 654763 AN: 1452630 Hom.: 159056 Cov.: 41 AF XY: 0.452 AC XY: 325709 AN XY: 720902

African (AFR) AF: 0.775 AC: 25754 AN: 33218

American (AMR) AF: 0.653 AC: 28829 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 8243 AN: 25888

East Asian (EAS) AF: 0.978 AC: 38594 AN: 39462

South Asian (SAS) AF: 0.588 AC: 50565 AN: 85924

European-Finnish (FIN) AF: 0.469 AC: 24963 AN: 53210

Middle Eastern (MID) AF: 0.340 AC: 1949 AN: 5726

European-Non Finnish (NFE) AF: 0.405 AC: 447833 AN: 1105140

Other (OTH) AF: 0.468 AC: 28033 AN: 59882

GnomAD4 genome AF: 0.542 AC: 82527 AN: 152144 Hom.: 25010 Cov.: 33 AF XY: 0.551 AC XY: 40988 AN XY: 74358

African (AFR) AF: 0.762 AC: 31641 AN: 41508

American (AMR) AF: 0.551 AC: 8419 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3472

East Asian (EAS) AF: 0.980 AC: 5077 AN: 5178

South Asian (SAS) AF: 0.623 AC: 3005 AN: 4822

European-Finnish (FIN) AF: 0.481 AC: 5087 AN: 10582

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26810 AN: 67978

Other (OTH) AF: 0.480 AC: 1013 AN: 2112

Alfa AF: 0.445 Hom.: 3054

Bravo AF: 0.559

Asia WGS AF: 0.793 AC: 2757 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fanconi anemia complementation group A Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.93
DANN	Benign	0.58
PhyloP100		-0.71
PromoterAI		-0.0043	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs7195906; hg19: chr16-89806347; COSMIC: COSV57065786; COSMIC: COSV57065786;