16-89739526-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_000135.4(FANCA):c.3962G>A(p.Arg1321His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,551,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1321C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.796

Publications

4 publications found

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]

FANCA links:

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]

ZNF276 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 30 uncertain in NM_000135.4

BP4

Computational evidence support a benign effect (MetaRNN=0.05760309).

BP6

Variant 16-89739526-C-T is Benign according to our data. Variant chr16-89739526-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456125.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCA	NM_000135.4	MANE Select	c.3962G>A	p.Arg1321His	missense	Exon 40 of 43	NP_000126.2
ZNF276	NM_001113525.2	MANE Select	c.*1280C>T		3_prime_UTR	Exon 11 of 11	NP_001106997.1
FANCA	NM_001286167.3		c.3962G>A	p.Arg1321His	missense	Exon 40 of 43	NP_001273096.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3962G>A	p.Arg1321His	missense	Exon 40 of 43	ENSP00000373952.3
ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*1280C>T		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2
ZNF276	ENST00000289816.9	TSL:1	c.*1280C>T		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000193

AC:

AN:

155550

AF XY:

0.0000122

show subpopulations

Gnomad AFR exome

AF:

0.000231

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1398998

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

690046

show subpopulations

African (AFR)

AF:

0.000316

AC:

AN:

31602

American (AMR)

AF:

0.0000560

AC:

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1079024

Other (OTH)

AF:

0.0000517

AC:

AN:

58004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41432

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Uncertain:2Benign:1

Jul 05, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Fanconi anemia complementation group A

Uncertain:1

Jul 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Feb 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, the variant has been reported in individuals with pancreatic cancer (PMID: 28767289 (2017)) and diffuse large B cell lymphoma (PMID: 23960188 (2013)).The frequency of this variant in the general population, 0.00023 (4/17352 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.1

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.12

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.75

M_CAP

Benign

0.048

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.4

PhyloP100

-0.80

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.44

REVEL

Benign

0.090

Sift

Benign

0.45

Sift4G

Benign

0.30

Polyphen

0.032

Vest4

0.065

MVP

0.90

ClinPred

0.044

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.096

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over