chr16-89740069-C-T

Variant names:

• chr16-89740069-C-T
• rs17227354
• NM_000135.4:c.3859G>A
• FANCA p.Val1287Ile

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.3859G>A​(p.Val1287Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,614,142 control chromosomes in the GnomAD database, including 290 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. V1287F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (149 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -1.79
• Publications: 14 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]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029883683).
• BP6: Variant 16-89740069-C-T is Benign according to our data. Variant chr16-89740069-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0814 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.3859G>A	p.Val1287Ile	missense	Exon 39 of 43	NP_000126.2	O15360-1
	ZNF276	NM_001113525.2	MANE Select	c.*1823C>T		3_prime_UTR	Exon 11 of 11	NP_001106997.1	Q8N554-1
	FANCA	NM_001286167.3		c.3859G>A	p.Val1287Ile	missense	Exon 39 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.3859G>A	p.Val1287Ile	missense	Exon 39 of 43	ENSP00000373952.3	O15360-1
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*1823C>T		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2	Q8N554-1
	ZNF276	ENST00000289816.9	TSL:1	c.*1823C>T		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5	Q8N554-2

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3937 AN: 152162 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00853 AC: 2146 AN: 251494 AF XY: 0.00685

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.00636

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00397 AC: 5798 AN: 1461862 Hom.: 149 Cov.: 33 AF XY: 0.00366 AC XY: 2659 AN XY: 727232

African (AFR) AF: 0.0871 AC: 2915 AN: 33478

American (AMR) AF: 0.00648 AC: 290 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00620 AC: 162 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00216 AC: 186 AN: 86258

European-Finnish (FIN) AF: 0.0102 AC: 545 AN: 53412

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5760

European-Non Finnish (NFE) AF: 0.00101 AC: 1124 AN: 1112002

Other (OTH) AF: 0.00753 AC: 455 AN: 60394

GnomAD4 genome AF: 0.0259 AC: 3948 AN: 152280 Hom.: 141 Cov.: 32 AF XY: 0.0251 AC XY: 1870 AN XY: 74466

African (AFR) AF: 0.0838 AC: 3480 AN: 41552

American (AMR) AF: 0.00980 AC: 150 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68012

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00948 Hom.: 116

Bravo AF: 0.0278

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00249

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)
-	-	4	not specified (5)
-	-	3	not provided (3)
-	-	1	Fanconi anemia (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0020
DANN	Benign	0.55
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.055	N
PhyloP100		-1.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.18
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
PromoterAI		-0.0011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.035
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17227354;

hg19: chr16-89806477;

COSMIC: COSV104614015;