10-126008488-C-T

Variant summary

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

The NM_145235.5(FANK1):c.787C>T(p.Leu263Phe) 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 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • 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: 2.05

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANK1	NM_145235.5	c.787C>T	p.Leu263Phe	missense_variant	8/11	ENST00000368693.6
FANK1	NM_001350939.2	c.865C>T	p.Leu289Phe	missense_variant	9/12
FANK1	NM_001363549.2	c.769C>T	p.Leu257Phe	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANK1	ENST00000368693.6	c.787C>T	p.Leu263Phe	missense_variant	8/11	1	NM_145235.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726982

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 28, 2024

The c.787C>T (p.L263F) alteration is located in exon 8 (coding exon 8) of the FANK1 gene. This alteration results from a C to T substitution at nucleotide position 787, causing the leucine (L) at amino acid position 263 to be replaced by a phenylalanine (F). 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	0.14
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0078	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.041	D;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.78	P;.;.
Vest4		0.50
MutPred		0.69		Gain of catalytic residue at L263 (P = 0.0361);.;.;
MVP		0.91
MPC		0.59
ClinPred		0.80	D
GERP RS		4.7
Varity_R		0.090
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-127697057;