rs12931267

Variant names:

• chr16-89752324-C-G
• rs12931267
• NM_000135.4:c.2982-102G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.2982-102G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 936,664 control chromosomes in the GnomAD database, including 2,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (210 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2091 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.507
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-89752324-C-G is Benign according to our data. Variant chr16-89752324-C-G is described in ClinVar as [Benign]. Clinvar id is 1267316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.2982-102G>C		intron_variant	Intron 30 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.2982-102G>C		intron_variant	Intron 30 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.2982-102G>C		intron_variant	Intron 30 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6954 AN: 152128 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0507

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0744

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0620 AC: 48670 AN: 784418 Hom.: 2091 AF XY: 0.0596 AC XY: 24822 AN XY: 416610

African (AFR) AF: 0.0122 AC: 251 AN: 20642

American (AMR) AF: 0.0106 AC: 460 AN: 43516

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 1483 AN: 21980

East Asian (EAS) AF: 0.0215 AC: 790 AN: 36672

South Asian (SAS) AF: 0.00496 AC: 362 AN: 72970

European-Finnish (FIN) AF: 0.0559 AC: 2329 AN: 41666

Middle Eastern (MID) AF: 0.00869 AC: 39 AN: 4488

European-Non Finnish (NFE) AF: 0.0809 AC: 40776 AN: 503924

Other (OTH) AF: 0.0565 AC: 2180 AN: 38560

GnomAD4 genome AF: 0.0457 AC: 6953 AN: 152246 Hom.: 210 Cov.: 32 AF XY: 0.0434 AC XY: 3234 AN XY: 74432

African (AFR) AF: 0.0150 AC: 623 AN: 41558

American (AMR) AF: 0.0168 AC: 257 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0744 AC: 258 AN: 3470

East Asian (EAS) AF: 0.0181 AC: 94 AN: 5180

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.0566 AC: 600 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4993 AN: 68008

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0703 Hom.: 248

Bravo AF: 0.0438

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.63
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs12931267; hg19: chr16-89818732;