chr16-89737589-T-C

Variant names:

• chr16-89737589-T-C
• rs886052477
• NM_000135.4:c.*1012A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000135.4(FANCA):​c.*1012A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 661,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FANCA NM_000135.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*1012A>G		3_prime_UTR	Exon 43 of 43	NP_000126.2	O15360-1
	ZNF276	NM_001113525.2	MANE Select	c.1475-217T>C		intron	N/A	NP_001106997.1	Q8N554-1
	FANCA	NM_001286167.3		c.*1109A>G		3_prime_UTR	Exon 43 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.*1012A>G		3_prime_UTR	Exon 43 of 43	ENSP00000373952.3	O15360-1
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.1475-217T>C		intron	N/A	ENSP00000415836.2	Q8N554-1
	ZNF276	ENST00000289816.9	TSL:1	c.1250-217T>C		intron	N/A	ENSP00000289816.5	Q8N554-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 1 AN: 661264 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 331684

African (AFR) AF: 0.00 AC: 0 AN: 16478

American (AMR) AF: 0.0000636 AC: 1 AN: 15724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14216

East Asian (EAS) AF: 0.00 AC: 0 AN: 29190

South Asian (SAS) AF: 0.00 AC: 0 AN: 43150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 482678

Other (OTH) AF: 0.00 AC: 0 AN: 31772

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia complementation group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.26
PhyloP100		1.0

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: rs886052477; hg19: chr16-89803997;