16-89745061-G-A

Variant names:

• chr16-89745061-G-A
• rs147017625
• NM_000135.4:c.3524C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000135.4(FANCA):​c.3524C>T​(p.Pro1175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,605,374 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1175S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4 O:1
• Conservation: PhyloP100: 3.27
• Publications: 4 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01314792).
• BP6: Variant 16-89745061-G-A is Benign according to our data. Variant chr16-89745061-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134268.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000735 (112/152282) while in subpopulation AFR AF = 0.00257 (107/41554). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.3524C>T	p.Pro1175Leu	missense	Exon 36 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3524C>T	p.Pro1175Leu	missense	Exon 36 of 43	NP_001273096.1	O15360-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3524C>T	p.Pro1175Leu	missense	Exon 36 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3524C>T	p.Pro1175Leu	missense	Exon 36 of 42	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3524C>T	p.Pro1175Leu	missense	Exon 36 of 43	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000301 AC: 71 AN: 235676 AF XY: 0.000272

Gnomad AFR exome AF: 0.00397

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000937

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1453092 Hom.: 2 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 722874

African (AFR) AF: 0.00381 AC: 127 AN: 33374

American (AMR) AF: 0.0000677 AC: 3 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.000315 AC: 27 AN: 85620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110600

Other (OTH) AF: 0.000183 AC: 11 AN: 60162

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74460

African (AFR) AF: 0.00257 AC: 107 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000229 Hom.: 1

Bravo AF: 0.000880

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia (2)
-	-	1	FANCA-related disorder (1)
-	1	-	Fanconi anemia complementation group A (1)
1	-	-	Hepatoblastoma (1)
-	-	1	not provided (1)
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.23	B
Vest4		0.18
MVP		0.92
ClinPred		0.076	T
GERP RS		3.5
PromoterAI		0.0062	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.17
gMVP		0.33
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs147017625; hg19: chr16-89811469; COSMIC: COSV57072734; COSMIC: COSV57072734;