rs17225943

Variant names:

• chr16-89803296-T-C
• rs17225943
• NM_000135.4:c.755A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-89803296-T-C
• chr16-89803296-T-G

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.755A>G​(p.Asp252Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,614,182 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (83 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (80 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.287
• 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: 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-89803296-T-C is Benign according to our data. Variant chr16-89803296-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 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.755A>G	p.Asp252Gly	missense	Exon 8 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.755A>G	p.Asp252Gly	missense	Exon 8 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.755A>G	p.Asp252Gly	missense	Exon 8 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.755A>G	p.Asp252Gly	missense	Exon 8 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.755A>G	p.Asp252Gly	missense	Exon 8 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.755A>G	p.Asp252Gly	missense	Exon 8 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2592 AN: 152200 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00452 AC: 1137 AN: 251424 AF XY: 0.00323

Gnomad AFR exome AF: 0.0625

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00173 AC: 2527 AN: 1461864 Hom.: 80 Cov.: 32 AF XY: 0.00147 AC XY: 1072 AN XY: 727234

African (AFR) AF: 0.0622 AC: 2082 AN: 33472

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1112000

Other (OTH) AF: 0.00366 AC: 221 AN: 60392

GnomAD4 genome AF: 0.0170 AC: 2591 AN: 152318 Hom.: 83 Cov.: 32 AF XY: 0.0164 AC XY: 1222 AN XY: 74486

African (AFR) AF: 0.0601 AC: 2496 AN: 41548

American (AMR) AF: 0.00451 AC: 69 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00697 Hom.: 56

Bravo AF: 0.0189

ESP6500AA AF: 0.0539 AC: 237

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00546 AC: 663

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group A (4)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.88
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.29
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.019
Sift	Benign	0.32	T
Sift4G	Benign	0.36	T
Polyphen		0.0050	B
Vest4		0.091
MVP		0.46
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.11
gMVP		0.22
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -37

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

Other links and lift over

dbSNP: rs17225943; hg19: chr16-89869704; COSMIC: COSV104699331;