rs17232616

chr16-89784971-G-A

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.1360-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,608,154 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (193 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (178 hom.)
• Consequence: FANCA NM_000135.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002991
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.24

Genes affected

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=-0.81).
• BP6: Variant 16-89784971-G-A is Benign according to our data. Variant chr16-89784971-G-A is described in ClinVar as [Benign]. Clinvar id is 321359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89784971-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1360-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.1360-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1360-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4255 AN: 152112 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00734 AC: 1843 AN: 251042 Hom.: 83 AF XY: 0.00553 AC XY: 750 AN XY: 135692

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00285 AC: 4145 AN: 1455924 Hom.: 178 Cov.: 29 AF XY: 0.00247 AC XY: 1790 AN XY: 724690

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000940

Gnomad4 OTH exome AF: 0.00605

GnomAD4 genome AF: 0.0280 AC: 4261 AN: 152230 Hom.: 193 Cov.: 32 AF XY: 0.0279 AC XY: 2076 AN XY: 74436

Gnomad4 AFR AF: 0.0977

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0154 Hom.: 43

Bravo AF: 0.0318

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jun 08, 2021

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.7
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0
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: rs17232616; hg19: chr16-89851379;