Genetic Variant NM_145235.5:c.138G>C (chr10-125980285-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_145235.5(FANK1):c.138G>C(p.Arg46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,614,014 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 79 hom., cov: 32)

Exomes 𝑓: 0.031 ( 838 hom. )

Consequence

FANK1
NM_145235.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.895

Publications

10 publications found

Variant links:

Genes affected

FANK1 (HGNC:23527): (fibronectin type III and ankyrin repeat domains 1) Involved in regulation of apoptotic process and regulation of transcription, DNA-templated. Located in cytosol and nucleoplasm. Colocalizes with chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FANK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00315395).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0235 (3575/152154) while in subpopulation NFE AF = 0.0331 (2247/67968). AF 95% confidence interval is 0.0319. There are 79 homozygotes in GnomAd4. There are 1684 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 79 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANK1	NM_145235.5	MANE Select	c.138G>C	p.Arg46Ser	missense	Exon 2 of 11	NP_660278.3
FANK1	NM_001350939.2		c.138G>C	p.Arg46Ser	missense	Exon 2 of 12	NP_001337868.1	Q8TC84-3
FANK1	NM_001363549.2		c.120G>C	p.Arg40Ser	missense	Exon 2 of 11	NP_001350478.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANK1	ENST00000368693.6	TSL:1 MANE Select	c.138G>C	p.Arg46Ser	missense	Exon 2 of 11	ENSP00000357682.1	Q8TC84-1
FANK1	ENST00000916275.1		c.138G>C	p.Arg46Ser	missense	Exon 2 of 12	ENSP00000586334.1
FANK1	ENST00000902356.1		c.138G>C	p.Arg46Ser	missense	Exon 2 of 10	ENSP00000572415.1

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3582

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00664

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00788

Gnomad FIN

AF:

0.0219

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0242

AC:

6094

AN:

251410

AF XY:

0.0244

show subpopulations

Gnomad AFR exome

AF:

0.00572

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0380

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0351

Gnomad OTH exome

AF:

0.0297

GnomAD4 exome

AF:

0.0308

AC:

45092

AN:

1461860

Hom.:

838

Cov.:

AF XY:

0.0303

AC XY:

22058

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00541

AC:

181

AN:

33478

American (AMR)

AF:

0.0230

AC:

1028

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

953

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00830

AC:

716

AN:

86250

European-Finnish (FIN)

AF:

0.0207

AC:

1104

AN:

53418

Middle Eastern (MID)

AF:

0.0218

AC:

126

AN:

5768

European-Non Finnish (NFE)

AF:

0.0352

AC:

39173

AN:

1111992

Other (OTH)

AF:

0.0300

AC:

1809

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2354

4707

7061

9414

11768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1446

2892

4338

5784

7230

<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:

0.0235

AC:

3575

AN:

152154

Hom.:

Cov.:

AF XY:

0.0226

AC XY:

1684

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00660

AC:

274

AN:

41532

American (AMR)

AF:

0.0295

AC:

451

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00768

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0219

AC:

232

AN:

10588

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0331

AC:

2247

AN:

67968

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

190

380

571

761

951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0320

Hom.:

Bravo

AF:

0.0239

TwinsUK

AF:

0.0356

AC:

132

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0349

AC:

300

ExAC

AF:

0.0240

AC:

2914

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0342

EpiControl

AF:

0.0369

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.010

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

0.90

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

REVEL

Benign

0.050

Sift

Benign

0.70

Sift4G

Benign

0.10

Polyphen

0.0010

Vest4

0.11

MutPred

0.20

Loss of helix (P = 0.0068)

MPC

0.16

ClinPred

0.0094

GERP RS

0.76

Varity_R

0.085

gMVP

0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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