rs17227064

Variant names:

• chr16-89749906-A-G
• rs17227064
• NM_000135.4:c.3067-4T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-89749906-A-G
• chr16-89749906-A-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.3067-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 1,613,692 control chromosomes in the GnomAD database, including 5,748 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 0.060 (417 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5331 hom.)
• Consequence: FANCA NM_000135.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004911
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.525
• Publications: 14 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
• 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=-0.82).
• BP6: Variant 16-89749906-A-G is Benign according to our data. Variant chr16-89749906-A-G is described in ClinVar as Benign. ClinVar VariationId is 255253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3067-4T>C		splice_region intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3067-4T>C		splice_region intron	N/A	NP_001273096.1	O15360-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3067-4T>C		splice_region intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3067-4T>C		splice_region intron	N/A	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3067-4T>C		splice_region intron	N/A	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9060 AN: 152188 Hom.: 416 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0564

GnomAD2 exomes AF: 0.0666 AC: 16741 AN: 251340 AF XY: 0.0658

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0767

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0790 AC: 115387 AN: 1461386 Hom.: 5331 Cov.: 32 AF XY: 0.0774 AC XY: 56291 AN XY: 727000

African (AFR) AF: 0.0113 AC: 379 AN: 33472

American (AMR) AF: 0.0211 AC: 944 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 1492 AN: 26136

East Asian (EAS) AF: 0.157 AC: 6248 AN: 39692

South Asian (SAS) AF: 0.0221 AC: 1903 AN: 86250

European-Finnish (FIN) AF: 0.0580 AC: 3098 AN: 53374

Middle Eastern (MID) AF: 0.0135 AC: 76 AN: 5638

European-Non Finnish (NFE) AF: 0.0866 AC: 96260 AN: 1111722

Other (OTH) AF: 0.0826 AC: 4987 AN: 60378

GnomAD4 genome AF: 0.0595 AC: 9067 AN: 152306 Hom.: 417 Cov.: 33 AF XY: 0.0575 AC XY: 4279 AN XY: 74476

African (AFR) AF: 0.0140 AC: 581 AN: 41576

American (AMR) AF: 0.0372 AC: 569 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1125 AN: 5178

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4828

European-Finnish (FIN) AF: 0.0613 AC: 651 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5667 AN: 68024

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.0592 Hom.: 164

Bravo AF: 0.0572

Asia WGS AF: 0.113 AC: 393 AN: 3478

EpiCase AF: 0.0748

EpiControl AF: 0.0730

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Fanconi anemia complementation group A (6)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.68
PhyloP100		-0.53
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0
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: rs17227064; hg19: chr16-89816314; COSMIC: COSV59795601;