rs1800347

chr16-89748641-T-C

Variant summary

Our verdict is Benign. Variant got -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:8
• Conservation: PhyloP100: -1.76

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 255255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89748641-T-C is described in Lovd as [Benign]. Variant chr16-89748641-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.3348+18A>G		intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.3348+18A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.3348+18A>G		intron_variant		1	NM_000135.4	P1

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

GnomAD3 exomes AF: 0.0261 AC: 6518 AN: 249980 Hom.: 126 AF XY: 0.0265 AC XY: 3580 AN XY: 135280

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 SAS exome AF: 0.00602

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

Gnomad4 AFR exome AF: 0.00646

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00681

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0452

Gnomad4 OTH exome AF: 0.0366

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

Gnomad4 AFR AF: 0.00842

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0275

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0357 Hom.: 31

Bravo AF: 0.0274

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Fanconi anemia Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.33
Dann	Benign	0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

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