16-89769915-C-T

Variant names:

• chr16-89769915-C-T
• rs7195066
• NM_000135.4:c.2426G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.2426G>A​(p.Gly809Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,742 control chromosomes in the GnomAD database, including 136,475 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G809V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (19562 hom., cov: 32)
  • Exomes 𝑓: 0.37 (116913 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12 O:1
• Conservation: PhyloP100: 0.0770
• Publications: 91 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-89769915-C-T is Benign according to our data. Variant chr16-89769915-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

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.2426G>A	p.Gly809Asp	missense	Exon 26 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.2426G>A	p.Gly809Asp	missense	Exon 26 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.2426G>A	p.Gly809Asp	missense	Exon 26 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.2426G>A		non_coding_transcript_exon	Exon 26 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.2426G>A	p.Gly809Asp	missense	Exon 26 of 42	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71730 AN: 151896 Hom.: 19532 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.473 AC: 118634 AN: 250996 AF XY: 0.461

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.372 AC: 544336 AN: 1461732 Hom.: 116913 Cov.: 52 AF XY: 0.376 AC XY: 273703 AN XY: 727164

African (AFR) AF: 0.678 AC: 22688 AN: 33476

American (AMR) AF: 0.636 AC: 28447 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6686 AN: 26136

East Asian (EAS) AF: 0.980 AC: 38922 AN: 39698

South Asian (SAS) AF: 0.587 AC: 50627 AN: 86254

European-Finnish (FIN) AF: 0.404 AC: 21539 AN: 53360

Middle Eastern (MID) AF: 0.322 AC: 1860 AN: 5768

European-Non Finnish (NFE) AF: 0.314 AC: 349350 AN: 1111930

Other (OTH) AF: 0.401 AC: 24217 AN: 60396

GnomAD4 genome AF: 0.472 AC: 71822 AN: 152010 Hom.: 19562 Cov.: 32 AF XY: 0.485 AC XY: 36049 AN XY: 74304

African (AFR) AF: 0.662 AC: 27445 AN: 41442

American (AMR) AF: 0.524 AC: 8001 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3470

East Asian (EAS) AF: 0.981 AC: 5065 AN: 5162

South Asian (SAS) AF: 0.623 AC: 3002 AN: 4820

European-Finnish (FIN) AF: 0.414 AC: 4367 AN: 10560

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21839 AN: 67970

Other (OTH) AF: 0.437 AC: 921 AN: 2108

Alfa AF: 0.368 Hom.: 55341

Bravo AF: 0.488

TwinsUK AF: 0.332 AC: 1232

ALSPAC AF: 0.316 AC: 1219

ESP6500AA AF: 0.659 AC: 2895

ESP6500EA AF: 0.314 AC: 2702

ExAC AF: 0.467 AC: 56751

Asia WGS AF: 0.781 AC: 2713 AN: 3478

EpiCase AF: 0.309

EpiControl AF: 0.302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	6	Fanconi anemia complementation group A (7)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Fanconi anemia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.21
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.084	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.077
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.20
Sift	Benign	0.53	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.045
ClinPred		0.00049	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7195066; hg19: chr16-89836323; COSMIC: COSV59796193; COSMIC: COSV59796193;