rs1800347

Variant names:

• chr16-89748641-T-C
• rs1800347
• NM_000135.4:c.3348+18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):​c.3348+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,596,320 control chromosomes in the GnomAD database, including 1,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (92 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1245 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -1.76
• 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=-0.96).
• BP6: Variant 16-89748641-T-C is Benign according to our data. Variant chr16-89748641-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0279 (4243/152310) while in subpopulation NFE AF = 0.0422 (2872/68016). AF 95% confidence interval is 0.0409. There are 92 homozygotes in GnomAd4. There are 1969 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3348+18A>G		intron	N/A	NP_000126.2
	FANCA	NM_001286167.3		c.3348+18A>G		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.3348+18A>G		intron	N/A	ENSP00000373952.3
	FANCA	ENST00000564475.6	TSL:2	c.3348+18A>G		intron	N/A	ENSP00000454977.2
	FANCA	ENST00000568369.6	TSL:2	c.3348+18A>G		intron	N/A	ENSP00000456829.1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4243 AN: 152192 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.00842

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0358

GnomAD2 exomes AF: 0.0261 AC: 6518 AN: 249980 AF XY: 0.0265

Gnomad AFR exome AF: 0.00631

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0403

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0385 AC: 55541 AN: 1444010 Hom.: 1245 Cov.: 28 AF XY: 0.0374 AC XY: 26892 AN XY: 719450

African (AFR) AF: 0.00646 AC: 214 AN: 33120

American (AMR) AF: 0.0225 AC: 1003 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 419 AN: 26010

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.00681 AC: 585 AN: 85914

European-Finnish (FIN) AF: 0.0276 AC: 1470 AN: 53170

Middle Eastern (MID) AF: 0.0260 AC: 149 AN: 5736

European-Non Finnish (NFE) AF: 0.0452 AC: 49510 AN: 1096002

Other (OTH) AF: 0.0366 AC: 2190 AN: 59784

GnomAD4 genome AF: 0.0279 AC: 4243 AN: 152310 Hom.: 92 Cov.: 33 AF XY: 0.0264 AC XY: 1969 AN XY: 74472

African (AFR) AF: 0.00842 AC: 350 AN: 41586

American (AMR) AF: 0.0355 AC: 543 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4826

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0422 AC: 2872 AN: 68016

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0327 Hom.: 204

Bravo AF: 0.0274

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Fanconi anemia complementation group A (5)
-	-	3	Fanconi anemia (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.33
DANN	Benign	0.15
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800347; hg19: chr16-89815049; COSMIC: COSV59797061;