16-89769943-C-A

Variant names:

• chr16-89769943-C-A
• rs1555547474
• NM_000135.4:c.2398G>T
• FANCA p.Glu800*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_000135.4(FANCA):c.2398G>T (p.Glu800*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCA NM_000135.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.787
• Publications: 1 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: Myriad Women's Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia, Natera
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 26 of 43) at amino acid 800 of 1455, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FANCA NM_000135.4	MANE Select	c.2398G>T p.Glu800*	stop_gained	Exon 26 of 43	Prot: NP_000126.2 UniProt:
	FANCA NM_001286167.3		c.2398G>T p.Glu800*	stop_gained	Exon 26 of 43	Prot: NP_001273096.1 UniProt:

FANCA NM_000135.4

MANE Select

HGVSc / HGVSpc.2398G>Tp.Glu800*

Exon rankExon 26 of 43

stop_gained

Prot: NP_000126.2UniProt: O15360-1

FANCA NM_001286167.3

HGVSc / HGVSpc.2398G>Tp.Glu800*

Exon rankExon 26 of 43

stop_gained

Prot: NP_001273096.1UniProt: O15360-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FANCA ENST00000389301.8	TSL:1MANE Select	c.2398G>T p.Glu800*	stop_gained	Exon 26 of 43	Prot: ENSP00000373952.3 UniProt:
	FANCA ENST00000567205.2	TSL:1	n.2398G>T	non_coding_transcript_exon	Exon 26 of 27	Prot: ENSP00000457027.2 UniProt:
	FANCA ENST00000564475.6	TSL:2	c.2398G>T p.Glu800*	stop_gained	Exon 26 of 42	Prot: ENSP00000454977.2 UniProt:

FANCA ENST00000389301.8

TSL:1MANE Select

HGVSc / HGVSpc.2398G>Tp.Glu800*

Exon rankExon 26 of 43

stop_gained

Prot: ENSP00000373952.3UniProt: O15360-1

FANCA ENST00000567205.2

TSL:1

HGVSc / HGVSpn.2398G>T

Exon rankExon 26 of 27

non_coding_transcript_exon

Prot: ENSP00000457027.2UniProt: H3BT53

FANCA ENST00000564475.6

TSL:2

HGVSc / HGVSpc.2398G>Tp.Glu800*

Exon rankExon 26 of 42

stop_gained

Prot: ENSP00000454977.2UniProt: H3BNS0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Fanconi anemia (2)
2	-	-	Fanconi anemia complementation group A (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.070	N
GPN-Star LLR	N/A	-7.3
GPN-Star score	N/A	7.3
Mutation Taster	N/A	2/198	disease causing (ClinVar)
PhyloP100	Benign	0.79

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555547474;

hg19: chr16-89836351;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar