rs55692229

Positions:

• chr16-89814594-T-A
• chr16-89814594-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000135.4(FANCA):​c.209A>T​(p.Lys70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.696

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33252162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4	c.209A>T	p.Lys70Ile	missense_variant	3/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.209A>T	p.Lys70Ile	missense_variant	3/43		NP_001273096.1
FANCA	NM_001018112.3	c.209A>T	p.Lys70Ile	missense_variant	3/11		NP_001018122.1
FANCA	NM_001351830.2	c.209A>T	p.Lys70Ile	missense_variant	3/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.209A>T	p.Lys70Ile	missense_variant	3/43	1	NM_000135.4	ENSP00000373952	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.;.;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.79	T;T;T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D
Polyphen		0.99	D;.;P;.;D;D
Vest4		0.45
MutPred		0.55		Loss of methylation at K70 (P = 0.0091);Loss of methylation at K70 (P = 0.0091);Loss of methylation at K70 (P = 0.0091);Loss of methylation at K70 (P = 0.0091);Loss of methylation at K70 (P = 0.0091);Loss of methylation at K70 (P = 0.0091);
MVP		0.69
ClinPred		0.68	D
GERP RS		3.9
Varity_R		0.18
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs55692229; hg19: chr16-89881002;