rs1555542910

Variant names:

• chr16-89758616-C-G
• rs1555542910
• NM_000135.4:c.2942G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-89758616-C-G
• chr16-89758616-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000135.4(FANCA):​c.2942G>C​(p.Cys981Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C981R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.19
• 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89758617-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224986.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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.2942G>C	p.Cys981Ser	missense	Exon 30 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.2942G>C	p.Cys981Ser	missense	Exon 30 of 43	NP_001273096.1	O15360-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.2942G>C	p.Cys981Ser	missense	Exon 30 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.2942G>C	p.Cys981Ser	missense	Exon 30 of 42	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.2942G>C	p.Cys981Ser	missense	Exon 30 of 43	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.76		Gain of disorder (P = 0.0276)
MVP		0.94
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.65
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs1555542910; hg19: chr16-89825024;