NM_000135.4:c.1226-20A>G

Variant names:

• chr16-89791556-T-C
• rs1800330
• NM_000135.4:c.1226-20A>G

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.1226-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,612,996 control chromosomes in the GnomAD database, including 123,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.43 (15206 hom., cov: 32)
  • Exomes 𝑓: 0.37 (108522 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.44
• Publications: 29 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 16-89791556-T-C is Benign according to our data. Variant chr16-89791556-T-C is described in ClinVar as Benign. ClinVar VariationId is 255232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1226-20A>G		intron_variant	Intron 13 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1226-20A>G		intron_variant	Intron 13 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1226-20A>G		intron_variant	Intron 13 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64622 AN: 151940 Hom.: 15190 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.441 AC: 109976 AN: 249494 AF XY: 0.433

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.753

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.367 AC: 535470 AN: 1460938 Hom.: 108522 Cov.: 47 AF XY: 0.370 AC XY: 268844 AN XY: 726768

African (AFR) AF: 0.562 AC: 18799 AN: 33470

American (AMR) AF: 0.620 AC: 27676 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6809 AN: 26126

East Asian (EAS) AF: 0.824 AC: 32691 AN: 39696

South Asian (SAS) AF: 0.565 AC: 48711 AN: 86190

European-Finnish (FIN) AF: 0.400 AC: 21233 AN: 53046

Middle Eastern (MID) AF: 0.321 AC: 1826 AN: 5694

European-Non Finnish (NFE) AF: 0.319 AC: 355158 AN: 1111704

Other (OTH) AF: 0.374 AC: 22567 AN: 60368

GnomAD4 genome AF: 0.425 AC: 64691 AN: 152058 Hom.: 15206 Cov.: 32 AF XY: 0.438 AC XY: 32581 AN XY: 74318

African (AFR) AF: 0.551 AC: 22848 AN: 41480

American (AMR) AF: 0.489 AC: 7472 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 917 AN: 3468

East Asian (EAS) AF: 0.764 AC: 3947 AN: 5164

South Asian (SAS) AF: 0.597 AC: 2883 AN: 4826

European-Finnish (FIN) AF: 0.407 AC: 4301 AN: 10556

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21187 AN: 67974

Other (OTH) AF: 0.381 AC: 806 AN: 2114

Alfa AF: 0.341 Hom.: 10157

Bravo AF: 0.438

Asia WGS AF: 0.665 AC: 2312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.10
DANN	Benign	0.53
PhyloP100		-5.4
BranchPoint Hunter		1.0
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)		0.010		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: rs1800330; hg19: chr16-89857964; COSMIC: COSV66881251;