NM_000135.4:c.3067-23G>A

Variant names:

• chr16-89749925-C-T
• rs17227057
• NM_000135.4:c.3067-23G>A

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.3067-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,612,260 control chromosomes in the GnomAD database, including 5,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (417 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5327 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.123
• Publications: 8 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=-0.9).
• BP6: Variant 16-89749925-C-T is Benign according to our data. Variant chr16-89749925-C-T is described in ClinVar as Benign. ClinVar VariationId is 255252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3067-23G>A		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.3067-23G>A		intron	N/A	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3067-23G>A		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000564475.6	TSL:2	c.3067-23G>A		intron	N/A	ENSP00000454977.2
	FANCA	ENST00000568369.6	TSL:2	c.3067-23G>A		intron	N/A	ENSP00000456829.1

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9062 AN: 152192 Hom.: 416 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0564

GnomAD2 exomes AF: 0.0666 AC: 16695 AN: 250704 AF XY: 0.0658

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.0767

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0787 AC: 114935 AN: 1459950 Hom.: 5327 Cov.: 32 AF XY: 0.0772 AC XY: 56094 AN XY: 726344

African (AFR) AF: 0.0113 AC: 378 AN: 33458

American (AMR) AF: 0.0211 AC: 944 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1488 AN: 26130

East Asian (EAS) AF: 0.157 AC: 6246 AN: 39690

South Asian (SAS) AF: 0.0220 AC: 1901 AN: 86218

European-Finnish (FIN) AF: 0.0580 AC: 3085 AN: 53180

Middle Eastern (MID) AF: 0.0138 AC: 74 AN: 5346

European-Non Finnish (NFE) AF: 0.0863 AC: 95843 AN: 1110894

Other (OTH) AF: 0.0825 AC: 4976 AN: 60316

GnomAD4 genome AF: 0.0595 AC: 9069 AN: 152310 Hom.: 417 Cov.: 33 AF XY: 0.0575 AC XY: 4279 AN XY: 74476

African (AFR) AF: 0.0140 AC: 580 AN: 41562

American (AMR) AF: 0.0373 AC: 570 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.217 AC: 1126 AN: 5188

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4832

European-Finnish (FIN) AF: 0.0613 AC: 651 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0833 AC: 5668 AN: 68032

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.0451 Hom.: 44

Bravo AF: 0.0572

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.35
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17227057; hg19: chr16-89816333; COSMIC: COSV59795607;