10-125980257-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145235.5(FANK1):​c.110G>A​(p.Arg37His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FANK1
NM_145235.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.98
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09983295).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANK1NM_145235.5 linkuse as main transcriptc.110G>A p.Arg37His missense_variant 2/11 ENST00000368693.6 NP_660278.3 Q8TC84-1
FANK1NM_001350939.2 linkuse as main transcriptc.110G>A p.Arg37His missense_variant 2/12 NP_001337868.1
FANK1NM_001363549.2 linkuse as main transcriptc.92G>A p.Arg31His missense_variant 2/11 NP_001350478.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANK1ENST00000368693.6 linkuse as main transcriptc.110G>A p.Arg37His missense_variant 2/111 NM_145235.5 ENSP00000357682.1 Q8TC84-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251450
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 11, 2022The c.110G>A (p.R37H) alteration is located in exon 2 (coding exon 2) of the FANK1 gene. This alteration results from a G to A substitution at nucleotide position 110, causing the arginine (R) at amino acid position 37 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0015
T;T;.;T;T;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.24
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.89
D;D;D;D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.10
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M;.;.;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.54
N;N;N;N;N;N
REVEL
Benign
0.21
Sift
Benign
0.59
T;T;T;T;T;T
Sift4G
Benign
0.11
T;T;T;D;T;D
Polyphen
0.99
D;.;.;.;.;.
Vest4
0.49
MutPred
0.43
Gain of loop (P = 0.0013);.;.;.;.;.;
MVP
0.36
MPC
0.45
ClinPred
0.29
T
GERP RS
4.0
Varity_R
0.030
gMVP
0.49

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs771570967; hg19: chr10-127668826; COSMIC: COSV64157126; API