rs17226337

Variant names:

• chr16-89779989-A-G
• rs17226337
• NM_000135.4:c.1627-32T>C

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -0.133
• Publications: 2 publications found

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]

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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.1627-32T>C		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.1627-32T>C		intron	N/A	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.1627-32T>C		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1627-32T>C		intron	N/A	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1627-32T>C		intron	N/A	ENSP00000454977.2

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

GnomAD2 exomes AF: 0.0195 AC: 4875 AN: 250046 AF XY: 0.0228

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 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

African (AFR) AF: 0.0177 AC: 584 AN: 33030

American (AMR) AF: 0.00649 AC: 290 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 465 AN: 26018

East Asian (EAS) AF: 0.00770 AC: 305 AN: 39600

South Asian (SAS) AF: 0.0831 AC: 7130 AN: 85810

European-Finnish (FIN) AF: 0.0125 AC: 668 AN: 53400

Middle Eastern (MID) AF: 0.0419 AC: 239 AN: 5702

European-Non Finnish (NFE) AF: 0.00717 AC: 7836 AN: 1092342

Other (OTH) AF: 0.0159 AC: 950 AN: 59716

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

African (AFR) AF: 0.0176 AC: 731 AN: 41578

American (AMR) AF: 0.00798 AC: 122 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5184

South Asian (SAS) AF: 0.0915 AC: 442 AN: 4828

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00931 AC: 633 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0134 Hom.: 5

Bravo AF: 0.0118

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group A (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.81
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17226337; hg19: chr16-89846397; COSMIC: COSV104699326;