rs189841793

chr16-89815999-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000135.4(FANCA):c.80-13C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,602,378 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (4 hom.)
• Consequence: FANCA NM_000135.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -0.473

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-89815999-G-A is Benign according to our data. Variant chr16-89815999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135542.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, not_provided=1, Uncertain_significance=1}. Variant chr16-89815999-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00117 (178/152366) while in subpopulation AMR AF= 0.00464 (71/15312). AF 95% confidence interval is 0.00377. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.80-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000389301.8
FANCA	NM_001018112.3	c.80-13C>T		splice_polypyrimidine_tract_variant, intron_variant
FANCA	NM_001286167.3	c.80-13C>T		splice_polypyrimidine_tract_variant, intron_variant
FANCA	NM_001351830.2	c.80-13C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.80-13C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152248 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000964 AC: 242 AN: 251132 Hom.: 2 AF XY: 0.00116 AC XY: 158 AN XY: 135842

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000766 AC: 1110 AN: 1450012 Hom.: 4 Cov.: 27 AF XY: 0.000828 AC XY: 598 AN XY: 722176

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000770

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152366 Hom.: 2 Cov.: 31 AF XY: 0.00133 AC XY: 99 AN XY: 74510

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000859 Hom.: 0

Bravo AF: 0.000986

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group A Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.98
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs189841793; hg19: chr16-89882407; COSMIC: COSV104699341; COSMIC: COSV104699341;