16-89810978-G-C

Variant names:

• chr16-89810978-G-C
• rs139160837
• NM_000135.4:c.377C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000135.4(FANCA):​c.377C>G​(p.Thr126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: -0.650
• Publications: 11 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006103754).
• BP6: Variant 16-89810978-G-C is Benign according to our data. Variant chr16-89810978-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408185.

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.377C>G	p.Thr126Arg	missense	Exon 4 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.377C>G	p.Thr126Arg	missense	Exon 4 of 43	NP_001273096.1	O15360-3
	FANCA	NM_001018112.3		c.377C>G	p.Thr126Arg	missense	Exon 4 of 11	NP_001018122.1	O15360-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.377C>G	p.Thr126Arg	missense	Exon 4 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000563673.5	TSL:1	c.377C>G	p.Thr126Arg	missense	Exon 4 of 10	ENSP00000456443.1	H3BRX3
	FANCA	ENST00000534992.5	TSL:1	c.377C>G	p.Thr126Arg	missense	Exon 4 of 11	ENSP00000443675.1	F5H8D5

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000438 AC: 110 AN: 251180 AF XY: 0.000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 727168

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000218 AC: 242 AN: 1112010

Other (OTH) AF: 0.000695 AC: 42 AN: 60394

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74476

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	3	Fanconi anemia (3)
-	3	-	Fanconi anemia complementation group A (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0070
DANN	Benign	0.35
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.65
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.043
Sift	Benign	0.51	T
Sift4G	Benign	0.49	T
Polyphen		0.035	B
Vest4		0.28
MVP		0.20
ClinPred		0.013	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
gMVP		0.062
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs139160837; hg19: chr16-89877386; COSMIC: COSV66881663; COSMIC: COSV66881663;