10-125996566-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145235.5(FANK1):c.415G>A(p.Val139Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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]

ACMG classification

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=0.20888981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANK1	NM_145235.5	c.415G>A	p.Val139Ile	missense_variant	5/11	ENST00000368693.6
FANK1	NM_001350939.2	c.493G>A	p.Val165Ile	missense_variant	6/12
FANK1	NM_001363549.2	c.397G>A	p.Val133Ile	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANK1	ENST00000368693.6	c.415G>A	p.Val139Ile	missense_variant	5/11	1	NM_145235.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.415G>A (p.V139I) alteration is located in exon 5 (coding exon 5) of the FANK1 gene. This alteration results from a G to A substitution at nucleotide position 415, causing the valine (V) at amino acid position 139 to be replaced by an isoleucine (I). 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	0.084
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0028	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.66	D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.062	T;T;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.25	B;.;.
Vest4		0.30
MutPred		0.25		Loss of ubiquitination at K142 (P = 0.1601);.;Loss of ubiquitination at K142 (P = 0.1601);
MVP		0.47
MPC		0.57
ClinPred		0.84	D
GERP RS		5.0
Varity_R		0.047
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1952346131; hg19: chr10-127685135;