rs1061646

chr16-89739569-G-Achr16-89739569-G-Cchr16-89739569-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):c.3935-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,550,080 control chromosomes in the GnomAD database, including 107,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14131 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93088 hom.)
• Consequence: FANCA NM_000135.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.398

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-89739569-G-A is Benign according to our data. Variant chr16-89739569-G-A is described in ClinVar as [Benign]. Clinvar id is 255264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89739569-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF276	NM_001113525.2	c.*1323G>A		3_prime_UTR_variant	11/11	ENST00000443381.7
FANCA	NM_000135.4	c.3935-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000389301.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF276	ENST00000443381.7	c.*1323G>A		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2
FANCA	ENST00000389301.8	c.3935-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62320 AN: 151940 Hom.: 14112 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.425 AC: 65869 AN: 155154 Hom.: 16003 AF XY: 0.417 AC XY: 34144 AN XY: 81922

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.613

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.725

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.349 AC: 487419 AN: 1398022 Hom.: 93088 Cov.: 35 AF XY: 0.350 AC XY: 241644 AN XY: 689600

Gnomad4 AFR exome AF: 0.546

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.808

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.388

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.410 AC: 62394 AN: 152058 Hom.: 14131 Cov.: 32 AF XY: 0.422 AC XY: 31343 AN XY: 74330

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.743

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.367

Alfa AF: 0.315 Hom.: 8974

Bravo AF: 0.425

Asia WGS AF: 0.610 AC: 2120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.0
Dann	Benign	0.44
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: rs1061646; hg19: chr16-89805977; COSMIC: COSV57068489; COSMIC: COSV57068489;