rs1800348

Variant names:

• chr16-89748630-G-A
• rs1800348
• NM_000135.4:c.3348+29C>T

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+29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,551,810 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (30 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.46
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 16-89748630-G-A is Benign according to our data. Variant chr16-89748630-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 255256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00375 (571/152318) while in subpopulation AMR AF = 0.00641 (98/15296). AF 95% confidence interval is 0.00538. There are 2 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3348+29C>T		intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3348+29C>T		intron	N/A	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.3348+29C>T		intron	N/A	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3348+29C>T		intron	N/A	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3348+29C>T		intron	N/A	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00514

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00410 AC: 1021 AN: 248722 AF XY: 0.00399

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00779

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00709

GnomAD4 exome AF: 0.00373 AC: 5215 AN: 1399492 Hom.: 30 Cov.: 24 AF XY: 0.00388 AC XY: 2713 AN XY: 699596

African (AFR) AF: 0.00198 AC: 64 AN: 32270

American (AMR) AF: 0.00488 AC: 217 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00871 AC: 224 AN: 25704

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39408

South Asian (SAS) AF: 0.00311 AC: 264 AN: 84942

European-Finnish (FIN) AF: 0.00484 AC: 256 AN: 52946

Middle Eastern (MID) AF: 0.0374 AC: 212 AN: 5664

European-Non Finnish (NFE) AF: 0.00347 AC: 3662 AN: 1055786

Other (OTH) AF: 0.00541 AC: 315 AN: 58260

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74478

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.00641 AC: 98 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 68024

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00639 Hom.: 1

Bravo AF: 0.00383

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.86
DANN	Benign	0.40
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1800348; hg19: chr16-89815038; COSMIC: COSV104619882;