rs11646374

Variant names:

• chr16-89791527-G-A
• rs11646374
• NM_000135.4:c.1235C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.1235C>T​(p.Ala412Val) variant causes a missense change. The variant allele was found at a frequency of 0.0769 in 1,613,900 control chromosomes in the GnomAD database, including 5,714 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. A412G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (413 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5301 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 4.09
• Publications: 41 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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 23 uncertain in NM_000135.4
• BP6: Variant 16-89791527-G-A is Benign according to our data. Variant chr16-89791527-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 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.1235C>T	p.Ala412Val	missense	Exon 14 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.1235C>T	p.Ala412Val	missense	Exon 14 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.1235C>T	p.Ala412Val	missense	Exon 14 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.1235C>T		non_coding_transcript_exon	Exon 14 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.1235C>T	p.Ala412Val	missense	Exon 14 of 42	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9001 AN: 152104 Hom.: 412 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0663 AC: 16631 AN: 250772 AF XY: 0.0654

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.0766

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0788 AC: 115169 AN: 1461678 Hom.: 5301 Cov.: 32 AF XY: 0.0772 AC XY: 56160 AN XY: 727132

African (AFR) AF: 0.0113 AC: 377 AN: 33478

American (AMR) AF: 0.0203 AC: 909 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 1490 AN: 26134

East Asian (EAS) AF: 0.157 AC: 6220 AN: 39690

South Asian (SAS) AF: 0.0220 AC: 1898 AN: 86248

European-Finnish (FIN) AF: 0.0573 AC: 3058 AN: 53332

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5760

European-Non Finnish (NFE) AF: 0.0865 AC: 96166 AN: 1111930

Other (OTH) AF: 0.0824 AC: 4975 AN: 60394

GnomAD4 genome AF: 0.0592 AC: 9007 AN: 152222 Hom.: 413 Cov.: 32 AF XY: 0.0570 AC XY: 4240 AN XY: 74428

African (AFR) AF: 0.0139 AC: 579 AN: 41550

American (AMR) AF: 0.0348 AC: 531 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3466

East Asian (EAS) AF: 0.216 AC: 1120 AN: 5174

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4822

European-Finnish (FIN) AF: 0.0613 AC: 650 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0832 AC: 5661 AN: 68002

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0748 Hom.: 1726

Bravo AF: 0.0568

TwinsUK AF: 0.0987 AC: 366

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.0812 AC: 698

ExAC AF: 0.0649 AC: 7878

Asia WGS AF: 0.109 AC: 376 AN: 3478

EpiCase AF: 0.0746

EpiControl AF: 0.0721

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group A (5)
-	-	3	not specified (4)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.089	T
Sift4G	Uncertain	0.034	D
Polyphen		0.95	P
Vest4		0.15
ClinPred		0.031	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.15
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11646374; hg19: chr16-89857935; COSMIC: COSV66880572; COSMIC: COSV66880572;