rs17226337

chr16-89779989-A-G

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.1627-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,592,614 control chromosomes in the GnomAD database, including 504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (40 hom., cov: 32)
  • Exomes 𝑓: 0.013 (464 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.133

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=-0.85).
• BP6: Variant 16-89779989-A-G is Benign according to our data. Variant chr16-89779989-A-G is described in ClinVar as [Benign]. Clinvar id is 255238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1627-32T>C		intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.1627-32T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1627-32T>C		intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2180 AN: 152202 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0195 AC: 4875 AN: 250046 Hom.: 158 AF XY: 0.0228 AC XY: 3084 AN XY: 135314

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00354

Gnomad SAS exome AF: 0.0856

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0128 AC: 18467 AN: 1440294 Hom.: 464 Cov.: 27 AF XY: 0.0151 AC XY: 10820 AN XY: 717984

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.00649

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00770

Gnomad4 SAS exome AF: 0.0831

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0144 AC: 2186 AN: 152320 Hom.: 40 Cov.: 32 AF XY: 0.0153 AC XY: 1138 AN XY: 74490

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.0915

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.00931

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0133 Hom.: 5

Bravo AF: 0.0118

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.4
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17226337; hg19: chr16-89846397; COSMIC: COSV104699326; COSMIC: COSV104699326;