16-89773344-C-T

Variant names:

• chr16-89773344-C-T
• rs17232917
• NM_000135.4:c.1941G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000135.4(FANCA):​c.1941G>A​(p.Glu647Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,551,564 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (238 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.74
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-89773344-C-T is Benign according to our data. Variant chr16-89773344-C-T is described in ClinVar as Benign. ClinVar VariationId is 255243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.1941G>A	p.Glu647Glu	synonymous	Exon 22 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.1941G>A	p.Glu647Glu	synonymous	Exon 22 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.1941G>A	p.Glu647Glu	synonymous	Exon 22 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.1941G>A		non_coding_transcript_exon	Exon 22 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.1941G>A	p.Glu647Glu	synonymous	Exon 22 of 42	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4914 AN: 152154 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.00742 AC: 1159 AN: 156252 AF XY: 0.00503

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00533

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00317 AC: 4434 AN: 1399292 Hom.: 238 Cov.: 31 AF XY: 0.00270 AC XY: 1861 AN XY: 690150

African (AFR) AF: 0.116 AC: 3666 AN: 31584

American (AMR) AF: 0.00613 AC: 219 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.000215 AC: 17 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49192

Middle Eastern (MID) AF: 0.00228 AC: 13 AN: 5698

European-Non Finnish (NFE) AF: 0.0000973 AC: 105 AN: 1078952

Other (OTH) AF: 0.00714 AC: 414 AN: 58002

GnomAD4 genome AF: 0.0323 AC: 4926 AN: 152272 Hom.: 278 Cov.: 32 AF XY: 0.0314 AC XY: 2339 AN XY: 74464

African (AFR) AF: 0.112 AC: 4652 AN: 41534

American (AMR) AF: 0.0121 AC: 185 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0117 Hom.: 63

Bravo AF: 0.0373

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.33
DANN	Benign	0.49
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs17232917; hg19: chr16-89839752; COSMIC: COSV104699390;