16-89745047-C-T

Variant names:

• chr16-89745047-C-T
• rs372706571
• NM_000135.4:c.3538G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):​c.3538G>A​(p.Val1180Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,607,800 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. V1180L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.846
• Publications: 3 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: ClinGen, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.008875608).
• BP6: Variant 16-89745047-C-T is Benign according to our data. Variant chr16-89745047-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000289 (44/152318) while in subpopulation SAS AF = 0.0087 (42/4828). AF 95% confidence interval is 0.00661. There are 1 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.3538G>A	p.Val1180Met	missense	Exon 36 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3538G>A	p.Val1180Met	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.3538G>A	p.Val1180Met	missense	Exon 36 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3538G>A	p.Val1180Met	missense	Exon 36 of 42	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3538G>A	p.Val1180Met	missense	Exon 36 of 43	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00128 AC: 310 AN: 241552 AF XY: 0.00164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000606 AC: 882 AN: 1455482 Hom.: 10 Cov.: 31 AF XY: 0.000871 AC XY: 631 AN XY: 724172

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00983 AC: 844 AN: 85890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48622

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111302

Other (OTH) AF: 0.000531 AC: 32 AN: 60220

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.7
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.85
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Benign	0.081	T
Polyphen		0.0090	B
Vest4		0.18
MutPred		0.28		Loss of catalytic residue at V1180 (P = 0.0624)
MVP		0.89
ClinPred		0.029	T
GERP RS		4.4
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.044
gMVP		0.32
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: rs372706571; hg19: chr16-89811455;