Genetic Variant NM_000135.4:c.3807G>C (chr16-89740825-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000135.4(FANCA):c.3807G>C(p.Leu1269Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0955 in 1,612,704 control chromosomes in the GnomAD database, including 8,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1269L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 977 hom., cov: 31)

Exomes 𝑓: 0.094 ( 7145 hom. )

Consequence

FANCA
NM_000135.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0120

Publications

24 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 16-89740825-C-G is Benign according to our data. Variant chr16-89740825-C-G is described in ClinVar as Benign. ClinVar VariationId is 255263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCA	NM_000135.4	MANE Select	c.3807G>C	p.Leu1269Leu	synonymous	Exon 38 of 43	NP_000126.2	O15360-1
ZNF276	NM_001113525.2	MANE Select	c.*2579C>G		3_prime_UTR	Exon 11 of 11	NP_001106997.1	Q8N554-1
FANCA	NM_001286167.3		c.3807G>C	p.Leu1269Leu	synonymous	Exon 38 of 43	NP_001273096.1	O15360-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3807G>C	p.Leu1269Leu	synonymous	Exon 38 of 43	ENSP00000373952.3	O15360-1
ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*2579C>G		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2	Q8N554-1
ZNF276	ENST00000289816.9	TSL:1	c.*2579C>G		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5	Q8N554-2

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15925

AN:

151874

Hom.:

974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0793

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0719

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0952

GnomAD2 exomes

AF:

0.0931

AC:

23291

AN:

250288

AF XY:

0.0930

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.0300

Gnomad ASJ exome

AF:

0.0770

Gnomad EAS exome

AF:

0.232

Gnomad FIN exome

AF:

0.0721

Gnomad NFE exome

AF:

0.0861

Gnomad OTH exome

AF:

0.0763

GnomAD4 exome

AF:

0.0945

AC:

138003

AN:

1460712

Hom.:

7145

Cov.:

AF XY:

0.0947

AC XY:

68803

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.143

AC:

4769

AN:

33452

American (AMR)

AF:

0.0331

AC:

1480

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

1971

AN:

26122

East Asian (EAS)

AF:

0.165

AC:

6541

AN:

39648

South Asian (SAS)

AF:

0.103

AC:

8904

AN:

86132

European-Finnish (FIN)

AF:

0.0705

AC:

3760

AN:

53356

Middle Eastern (MID)

AF:

0.0570

AC:

329

AN:

5768

European-Non Finnish (NFE)

AF:

0.0936

AC:

103964

AN:

1111188

Other (OTH)

AF:

0.104

AC:

6285

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

5966

11931

17897

23862

29828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3962

7924

11886

15848

19810

<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:

0.105

AC:

15943

AN:

151992

Hom.:

977

Cov.:

AF XY:

0.102

AC XY:

7598

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.140

AC:

5785

AN:

41400

American (AMR)

AF:

0.0549

AC:

838

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0793

AC:

275

AN:

3468

East Asian (EAS)

AF:

0.224

AC:

1159

AN:

5176

South Asian (SAS)

AF:

0.119

AC:

573

AN:

4808

European-Finnish (FIN)

AF:

0.0719

AC:

760

AN:

10576

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0929

AC:

6319

AN:

67994

Other (OTH)

AF:

0.0952

AC:

201

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

690

1380

2070

2760

3450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.0660

Hom.:

144

Bravo

AF:

0.105

Asia WGS

AF:

0.166

AC:

577

AN:

3478

EpiCase

AF:

0.0884

EpiControl

AF:

0.0845

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group A (5)

not provided (2)

Fanconi anemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.53

(source)

DANN

Benign

0.63

PhyloP100

-0.012

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over