rs1800347

Positions:

chr16-89748641-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -1.76

Variant links:

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 links:

FANCA (HGNC:):

FANCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.3348+18A>G		intron_variant		ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 linkuse as main transcript	c.3348+18A>G		intron_variant			NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3348+18A>G		intron_variant		1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0279

AC:

4243

AN:

152192

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0374

AC XY:

26892

AN XY:

719450

show subpopulations

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.:

Cov.:

AF XY:

0.0264

AC XY:

1969

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.0274

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Uncertain:1Benign:2

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

Fanconi anemia

Benign:3

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

not specified

Benign:2

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

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over