rs45441106

chr16-89770570-G-Achr16-89770570-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000135.4(FANCA):c.2216C>T(p.Pro739Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,609,406 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P739R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00088 (5 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 3.32

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01083675).
• BP6: Variant 16-89770570-G-A is Benign according to our data. Variant chr16-89770570-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00298 (453/152252) while in subpopulation AFR AF= 0.00956 (397/41532). AF 95% confidence interval is 0.00878. There are 1 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.2216C>T	p.Pro739Leu	missense_variant	24/43	ENST00000389301.8
FANCA	NM_001286167.3	c.2216C>T	p.Pro739Leu	missense_variant	24/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.2216C>T	p.Pro739Leu	missense_variant	24/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152134 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00954

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000926 AC: 223 AN: 240854 Hom.: 0 AF XY: 0.000704 AC XY: 92 AN XY: 130630

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.000198

Gnomad NFE exome AF: 0.000451

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000882 AC: 1285 AN: 1457154 Hom.: 5 Cov.: 32 AF XY: 0.000805 AC XY: 583 AN XY: 724440

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000430

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0000822

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000761

Gnomad4 OTH exome AF: 0.000848

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152252 Hom.: 1 Cov.: 31 AF XY: 0.00285 AC XY: 212 AN XY: 74464

Gnomad4 AFR AF: 0.00956

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000817 Hom.: 1

Bravo AF: 0.00328

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00751 AC: 33

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 23, 2021	- -

Fanconi anemia complementation group A Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28678401) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FANCA: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0078	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.018	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.49
MVP		0.98
ClinPred		0.064	T
GERP RS		4.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.26
gMVP		0.52

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: rs45441106; hg19: chr16-89836978;