chr16-89816551-C-G

Variant names:

• chr16-89816551-C-G
• rs761341952
• NM_000135.4:c.65G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000135.4(FANCA):​c.65G>C​(p.Trp22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,509,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.325
• Publications: 6 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: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.65G>C	p.Trp22Ser	missense	Exon 1 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.65G>C	p.Trp22Ser	missense	Exon 1 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.65G>C	p.Trp22Ser	missense	Exon 1 of 11	NP_001018122.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.65G>C	p.Trp22Ser	missense	Exon 1 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.65G>C	p.Trp22Ser	missense	Exon 1 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.65G>C	p.Trp22Ser	missense	Exon 1 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1357234 Hom.: 0 Cov.: 30 AF XY: 0.00000448 AC XY: 3 AN XY: 669956

African (AFR) AF: 0.00 AC: 0 AN: 27704

American (AMR) AF: 0.00 AC: 0 AN: 33552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24176

East Asian (EAS) AF: 0.00 AC: 0 AN: 32200

South Asian (SAS) AF: 0.00 AC: 0 AN: 76750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4500

European-Non Finnish (NFE) AF: 0.00000468 AC: 5 AN: 1068494

Other (OTH) AF: 0.00 AC: 0 AN: 56446

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.33
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.48		Gain of phosphorylation at W22 (P = 0.0052)
MVP		0.88
ClinPred		0.79	D
GERP RS		1.1
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.13
Mutation Taster		=96/4	polymorphism

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: rs761341952; hg19: chr16-89882959;