chr16-89808348-G-A

Variant names:

• chr16-89808348-G-A
• rs17232246
• NM_000135.4:c.542C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.542C>T​(p.Ala181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,613,960 control chromosomes in the GnomAD database, including 1,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (576 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (532 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10 O:1
• Conservation: PhyloP100: 1.00
• Publications: 11 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: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• 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 (MetaRNN=0.0019883811).
• BP6: Variant 16-89808348-G-A is Benign according to our data. Variant chr16-89808348-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

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.542C>T	p.Ala181Val	missense	Exon 6 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.542C>T	p.Ala181Val	missense	Exon 6 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.542C>T	p.Ala181Val	missense	Exon 6 of 11	NP_001018122.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.542C>T	p.Ala181Val	missense	Exon 6 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.542C>T	p.Ala181Val	missense	Exon 6 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.542C>T	p.Ala181Val	missense	Exon 6 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6977 AN: 152004 Hom.: 574 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0122 AC: 3069 AN: 251326 AF XY: 0.00849

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00741

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00474 AC: 6928 AN: 1461838 Hom.: 532 Cov.: 32 AF XY: 0.00401 AC XY: 2916 AN XY: 727218

African (AFR) AF: 0.167 AC: 5574 AN: 33460

American (AMR) AF: 0.00809 AC: 362 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1111990

Other (OTH) AF: 0.0102 AC: 614 AN: 60394

GnomAD4 genome AF: 0.0459 AC: 6986 AN: 152122 Hom.: 576 Cov.: 33 AF XY: 0.0442 AC XY: 3284 AN XY: 74366

African (AFR) AF: 0.160 AC: 6641 AN: 41466

American (AMR) AF: 0.0151 AC: 230 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68010

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0157 Hom.: 576

Bravo AF: 0.0522

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.168 AC: 738

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0153 AC: 1853

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	5	Fanconi anemia complementation group A (6)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Benign	0.25	T
Sift4G	Uncertain	0.047	D
Polyphen		0.91	P
Vest4		0.20
ClinPred		0.0095	T
GERP RS		2.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.025
gMVP		0.064
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17232246; hg19: chr16-89874756; COSMIC: COSV104699332;