rs17227361

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP6_Very_StrongBS1

The NM_000135.4(FANCA):​c.3891G>A​(p.Lys1297Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,614,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

FANCA
NM_000135.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.61
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 16-89740037-C-T is Benign according to our data. Variant chr16-89740037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414831.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 = 0.00263 (401/152332) while in subpopulation AFR AF= 0.00912 (379/41576). AF 95% confidence interval is 0.00836. There are 0 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCANM_000135.4 linkuse as main transcriptc.3891G>A p.Lys1297Lys synonymous_variant 39/43 ENST00000389301.8 NP_000126.2 O15360-1
ZNF276NM_001113525.2 linkuse as main transcriptc.*1791C>T 3_prime_UTR_variant 11/11 ENST00000443381.7 NP_001106997.1 Q8N554-1I6L9I3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCAENST00000389301.8 linkuse as main transcriptc.3891G>A p.Lys1297Lys synonymous_variant 39/431 NM_000135.4 ENSP00000373952.3 O15360-1
ZNF276ENST00000443381.7 linkuse as main transcriptc.*1791C>T 3_prime_UTR_variant 11/111 NM_001113525.2 ENSP00000415836.2 Q8N554-1

Frequencies

GnomAD3 genomes
AF:
0.00264
AC:
402
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00917
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000712
AC:
179
AN:
251492
Hom.:
0
AF XY:
0.000456
AC XY:
62
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00960
Gnomad AMR exome
AF:
0.000463
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000283
AC:
414
AN:
1461880
Hom.:
1
Cov.:
33
AF XY:
0.000246
AC XY:
179
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0103
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.00263
AC:
401
AN:
152332
Hom.:
0
Cov.:
32
AF XY:
0.00254
AC XY:
189
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.00912
Gnomad4 AMR
AF:
0.000981
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00116
Hom.:
0
Bravo
AF:
0.00305
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia Benign:3
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Dec 09, 2019- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Dec 15, 2020- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 04, 2021- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 26, 2021- -
Fanconi anemia complementation group A Benign:2
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 23, 2021- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
4.1
DANN
Benign
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.28
Position offset: -43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17227361; hg19: chr16-89806445; API