NM_000135.4:c.1874G>C

Variant names:

• chr16-89775768-C-G
• rs139235751
• NM_000135.4:c.1874G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_000135.4(FANCA):​c.1874G>C​(p.Cys625Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00258 in 1,612,748 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts 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. C625Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:9
• Conservation: PhyloP100: 4.72
• Publications: 20 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: ClinGen, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.19460729).
• BP6: Variant 16-89775768-C-G is Benign according to our data. Variant chr16-89775768-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265136.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00222 (338/152300) while in subpopulation NFE AF = 0.00392 (267/68028). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.1874G>C	p.Cys625Ser	missense	Exon 21 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.1874G>C	p.Cys625Ser	missense	Exon 21 of 43	NP_001273096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.1874G>C	p.Cys625Ser	missense	Exon 21 of 43	ENSP00000373952.3
	FANCA	ENST00000567205.2	TSL:1	n.1874G>C		non_coding_transcript_exon	Exon 21 of 27	ENSP00000457027.2
	FANCA	ENST00000564475.6	TSL:2	c.1874G>C	p.Cys625Ser	missense	Exon 21 of 42	ENSP00000454977.2

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00236 AC: 587 AN: 249194 AF XY: 0.00235

Gnomad AFR exome AF: 0.000749

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00262 AC: 3820 AN: 1460448 Hom.: 9 Cov.: 30 AF XY: 0.00259 AC XY: 1884 AN XY: 726338

African (AFR) AF: 0.000389 AC: 13 AN: 33452

American (AMR) AF: 0.00173 AC: 77 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.000844 AC: 22 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000955 AC: 82 AN: 85882

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53326

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00308 AC: 3423 AN: 1111356

Other (OTH) AF: 0.00217 AC: 131 AN: 60342

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74470

African (AFR) AF: 0.000722 AC: 30 AN: 41550

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00392 AC: 267 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00219

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00291

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	4	2	Fanconi anemia complementation group A (7)
-	3	3	not specified (6)
-	2	1	not provided (3)
-	-	2	Fanconi anemia (2)
-	-	1	FANCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.19	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.58		Gain of disorder (P = 0.0348)
MVP		0.96
ClinPred		0.096	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.74
gMVP		0.70
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs139235751; hg19: chr16-89842176;