rs760787108

Positions:

• chr16-89815979-C-A
• chr16-89815979-C-G
• chr16-89815979-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000135.4(FANCA):​c.87G>T​(p.Arg29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.87G>T	p.Arg29Ser	missense_variant	2/43	ENST00000389301.8
FANCA	NM_001286167.3	c.87G>T	p.Arg29Ser	missense_variant	2/43
FANCA	NM_001018112.3	c.87G>T	p.Arg29Ser	missense_variant	2/11
FANCA	NM_001351830.2	c.87G>T	p.Arg29Ser	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.87G>T	p.Arg29Ser	missense_variant	2/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	2.0	M;M;M;.;.;.
MutationTaster	Benign	0.52	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.012	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D
Vest4		0.81
MutPred		0.35		Gain of glycosylation at R29 (P = 0.0167);Gain of glycosylation at R29 (P = 0.0167);Gain of glycosylation at R29 (P = 0.0167);Gain of glycosylation at R29 (P = 0.0167);Gain of glycosylation at R29 (P = 0.0167);Gain of glycosylation at R29 (P = 0.0167);
MVP		0.96
ClinPred		0.97	D
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.30
gMVP		0.31

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: rs760787108; hg19: chr16-89882387;