rs1443680543

Variant names:

• chr16-89740834-C-T
• rs1443680543
• NM_000135.4:c.3798G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000135.4(FANCA):​c.3798G>A​(p.Met1266Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.603
• 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]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.3798G>A	p.Met1266Ile	missense	Exon 38 of 43	NP_000126.2
	ZNF276	NM_001113525.2	MANE Select	c.*2588C>T		3_prime_UTR	Exon 11 of 11	NP_001106997.1
	FANCA	NM_001286167.3		c.3798G>A	p.Met1266Ile	missense	Exon 38 of 43	NP_001273096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3798G>A	p.Met1266Ile	missense	Exon 38 of 43	ENSP00000373952.3
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*2588C>T		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2
	ZNF276	ENST00000289816.9	TSL:1	c.*2588C>T		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250758 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111756

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.035
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.60
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.79
Sift	Benign	0.14	T
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.68
MutPred		0.73		Loss of disorder (P = 0.0924)
MVP		0.79
ClinPred		0.38	T
GERP RS		2.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.077
gMVP		0.29
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.82		Position offset: -2

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

Other links and lift over

dbSNP: rs1443680543; hg19: chr16-89807242;