16-89737590-G-A

Variant names:

• chr16-89737590-G-A
• rs17227452
• NM_000135.4:c.*1011C>T

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.*1011C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 816,526 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (26 hom.)
• Consequence: FANCA NM_000135.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.808
• 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]

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 (BayesDel_noAF=-0.91).
• BP6: Variant 16-89737590-G-A is Benign according to our data. Variant chr16-89737590-G-A is described in ClinVar as Benign. ClinVar VariationId is 321303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 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.*1011C>T		3_prime_UTR	Exon 43 of 43	NP_000126.2	O15360-1
	ZNF276	NM_001113525.2	MANE Select	c.1475-216G>A		intron	N/A	NP_001106997.1	Q8N554-1
	FANCA	NM_001286167.3		c.*1108C>T		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.*1011C>T		3_prime_UTR	Exon 43 of 43	ENSP00000373952.3	O15360-1
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.1475-216G>A		intron	N/A	ENSP00000415836.2	Q8N554-1
	ZNF276	ENST00000289816.9	TSL:1	c.1250-216G>A		intron	N/A	ENSP00000289816.5	Q8N554-2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2341 AN: 152028 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.00167 AC: 1109 AN: 664390 Hom.: 26 Cov.: 9 AF XY: 0.00144 AC XY: 480 AN XY: 333444

African (AFR) AF: 0.0575 AC: 949 AN: 16506

American (AMR) AF: 0.00241 AC: 39 AN: 16150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14280

East Asian (EAS) AF: 0.00 AC: 0 AN: 29364

South Asian (SAS) AF: 0.000182 AC: 8 AN: 44022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25792

Middle Eastern (MID) AF: 0.00128 AC: 3 AN: 2344

European-Non Finnish (NFE) AF: 0.0000248 AC: 12 AN: 483940

Other (OTH) AF: 0.00306 AC: 98 AN: 31992

GnomAD4 genome AF: 0.0154 AC: 2342 AN: 152136 Hom.: 59 Cov.: 32 AF XY: 0.0148 AC XY: 1099 AN XY: 74376

African (AFR) AF: 0.0540 AC: 2243 AN: 41502

American (AMR) AF: 0.00451 AC: 69 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00999 AC: 21 AN: 2102

Alfa AF: 0.0103 Hom.: 17

Bravo AF: 0.0173

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.50
PhyloP100		-0.81
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: rs17227452; hg19: chr16-89803998;