rs75501942

Variant names:

• chr16-89795980-A-G
• rs75501942
• NM_000135.4:c.932T>C

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.932T>C​(p.Ile311Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,614,184 control chromosomes in the GnomAD database, including 10 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. I311F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.80
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072969496).
• BP6: Variant 16-89795980-A-G is Benign according to our data. Variant chr16-89795980-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134240.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 = 0.00312 (475/152322) while in subpopulation AFR AF = 0.0105 (438/41580). AF 95% confidence interval is 0.00972. There are 5 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.932T>C	p.Ile311Thr	missense	Exon 11 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.932T>C	p.Ile311Thr	missense	Exon 11 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.932T>C	p.Ile311Thr	missense	Exon 11 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000566409.1	TSL:1	n.*196T>C		non_coding_transcript_exon	Exon 2 of 2	ENSP00000457647.1	H3BUI1
	FANCA	ENST00000567205.2	TSL:1	n.932T>C		non_coding_transcript_exon	Exon 11 of 27	ENSP00000457027.2	H3BT53

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152204 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00102 AC: 256 AN: 251454 AF XY: 0.000831

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461862 Hom.: 5 Cov.: 31 AF XY: 0.000461 AC XY: 335 AN XY: 727234

African (AFR) AF: 0.0132 AC: 443 AN: 33474

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 125 AN: 1111994

Other (OTH) AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152322 Hom.: 5 Cov.: 33 AF XY: 0.00315 AC XY: 235 AN XY: 74486

African (AFR) AF: 0.0105 AC: 438 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00116 Hom.: 6

Bravo AF: 0.00364

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group A (4)
-	-	3	not specified (4)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.58
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.050
Sift	Benign	0.094	T
Sift4G	Benign	0.12	T
Polyphen		0.024	B
Vest4		0.18
MVP		0.49
ClinPred		0.0047	T
GERP RS		2.8
Varity_R		0.033
gMVP		0.27
Mutation Taster		=100/0	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: rs75501942; hg19: chr16-89862388; COSMIC: COSV104699347;