rs17227191

Variant names:

• chr16-89746798-A-G
• rs17227191
• NM_000135.4:c.3408+33T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000389301.8(FANCA):​c.3408+33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,576,166 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (68 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (47 hom.)
• Consequence: FANCA ENST00000389301.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0340
• 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=-0.89).
• BP6: Variant 16-89746798-A-G is Benign according to our data. Variant chr16-89746798-A-G is described in ClinVar as Benign. ClinVar VariationId is 255257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000389301.8. 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.3408+33T>C		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.3408+33T>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.3408+33T>C		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000564475.6	TSL:2	c.3408+33T>C		intron	N/A	ENSP00000454977.2
	FANCA	ENST00000568369.6	TSL:2	c.3408+33T>C		intron	N/A	ENSP00000456829.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2638 AN: 152180 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00565 AC: 1067 AN: 188792 AF XY: 0.00465

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00479

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00271 AC: 3862 AN: 1423868 Hom.: 47 Cov.: 31 AF XY: 0.00255 AC XY: 1801 AN XY: 704994

African (AFR) AF: 0.0544 AC: 1766 AN: 32450

American (AMR) AF: 0.00412 AC: 158 AN: 38372

Ashkenazi Jewish (ASJ) AF: 0.00553 AC: 141 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 37588

South Asian (SAS) AF: 0.00169 AC: 139 AN: 82298

European-Finnish (FIN) AF: 0.0101 AC: 518 AN: 51124

Middle Eastern (MID) AF: 0.0107 AC: 61 AN: 5708

European-Non Finnish (NFE) AF: 0.000724 AC: 790 AN: 1091808

Other (OTH) AF: 0.00489 AC: 289 AN: 59040

GnomAD4 genome AF: 0.0173 AC: 2642 AN: 152298 Hom.: 68 Cov.: 33 AF XY: 0.0170 AC XY: 1265 AN XY: 74468

African (AFR) AF: 0.0546 AC: 2271 AN: 41570

American (AMR) AF: 0.00595 AC: 91 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68030

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0111 Hom.: 11

Bravo AF: 0.0180

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.56
DANN	Benign	0.65
PhyloP100		-0.034
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17227191; hg19: chr16-89813206; COSMIC: COSV104619843;