NM_000135.4:c.2398_2400delGAGinsAAA

Variant names:

• chr16-89769941-CTC-TTT
• NM_000135.4:c.2398_2400delGAGinsAAA
• FANCA p.Glu800Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000135.4(FANCA):c.2398_2400delGAGinsAAA (p.Glu800Lys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E800G: Uncertain_significance (ClinVar VariationId 990014, 2 stars); p.E800Q: Uncertain_significance (ClinVar VariationId 3848144, 1 star); p.E800V: Uncertain_significance (ClinVar VariationId 1463772, 1 star)

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.787
• Publications: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.

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.2398_2400delGAGinsAAA p.Glu800Lys	missense	N/A	Prot: NP_000126.2 UniProt:
	FANCA NM_001286167.3		c.2398_2400delGAGinsAAA p.Glu800Lys	missense	N/A	Prot: NP_001273096.1 UniProt:

FANCA NM_000135.4

MANE Select

HGVSc / HGVSpc.2398_2400delGAGinsAAAp.Glu800Lys

Exon rankN/A

missense

Prot: NP_000126.2UniProt: O15360-1

FANCA NM_001286167.3

HGVSc / HGVSpc.2398_2400delGAGinsAAAp.Glu800Lys

Exon rankN/A

missense

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.2398_2400delGAGinsAAA p.Glu800Lys	missense	N/A	Prot: ENSP00000373952.3 UniProt:
	FANCA ENST00000567205.2	TSL:1	n.2398_2400delGAGinsAAA	non_coding_transcript_exon	Exon 26 of 27	Prot: ENSP00000457027.2 UniProt:
	FANCA ENST00000564475.6	TSL:2	c.2398_2400delGAGinsAAA p.Glu800Lys	missense	N/A	Prot: ENSP00000454977.2 UniProt:

FANCA ENST00000389301.8

TSL:1MANE Select

HGVSc / HGVSpc.2398_2400delGAGinsAAAp.Glu800Lys

Exon rankN/A

missense

Prot: ENSP00000373952.3UniProt: O15360-1

FANCA ENST00000567205.2

TSL:1

HGVSc / HGVSpn.2398_2400delGAGinsAAA

Exon rankExon 26 of 27

non_coding_transcript_exon

Prot: ENSP00000457027.2UniProt: H3BT53

FANCA ENST00000564475.6

TSL:2

HGVSc / HGVSpc.2398_2400delGAGinsAAAp.Glu800Lys

Exon rankN/A

missense

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.79

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr16-89836349;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar