NM_000135.4:c.2398G>A

Variant names:

• chr16-89769943-C-T
• rs1555547474
• NM_000135.4:c.2398G>A
• FANCA p.Glu800Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000135.4(FANCA):c.2398G>A (p.Glu800Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,718 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (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.2398G>A p.Glu800Lys	missense	Exon 26 of 43	Prot: NP_000126.2 UniProt:
	FANCA NM_001286167.3		c.2398G>A p.Glu800Lys	missense	Exon 26 of 43	Prot: NP_001273096.1 UniProt:

FANCA NM_000135.4

MANE Select

HGVSc / HGVSpc.2398G>Ap.Glu800Lys

Exon rankExon 26 of 43

missense

Prot: NP_000126.2UniProt: O15360-1

FANCA NM_001286167.3

HGVSc / HGVSpc.2398G>Ap.Glu800Lys

Exon rankExon 26 of 43

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.2398G>A p.Glu800Lys	missense	Exon 26 of 43	Prot: ENSP00000373952.3 UniProt:
	FANCA ENST00000567205.2	TSL:1	n.2398G>A	non_coding_transcript_exon	Exon 26 of 27	Prot: ENSP00000457027.2 UniProt:
	FANCA ENST00000564475.6	TSL:2	c.2398G>A p.Glu800Lys	missense	Exon 26 of 42	Prot: ENSP00000454977.2 UniProt:

FANCA ENST00000389301.8

TSL:1MANE Select

HGVSc / HGVSpc.2398G>Ap.Glu800Lys

Exon rankExon 26 of 43

missense

Prot: ENSP00000373952.3UniProt: O15360-1

FANCA ENST00000567205.2

TSL:1

HGVSc / HGVSpn.2398G>A

Exon rankExon 26 of 27

non_coding_transcript_exon

Prot: ENSP00000457027.2UniProt: H3BT53

FANCA ENST00000564475.6

TSL:2

HGVSc / HGVSpc.2398G>Ap.Glu800Lys

Exon rankExon 26 of 42

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461718	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.4
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.6
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
FuncVEP CTI	Benign	0.017
GPN-Star LLR	N/A	-3.6
GPN-Star score	N/A	3.6
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.80	T
Mutation Taster	N/A	92/8	polymorphism
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	0.79
popEVE	Benign	-3.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.083
Sift	Benign	0.24	T
Sift4G	Benign	0.29	T
Varity_R	N/A	0.035
VESM-3B	Benign	-6.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	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