10-125988628-C-T

Position:

• chr10-125988628-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145235.5(FANK1):​c.269C>T​(p.Pro90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33992177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANK1	NM_145235.5	c.269C>T	p.Pro90Leu	missense_variant	3/11	ENST00000368693.6
FANK1	NM_001350939.2	c.269C>T	p.Pro90Leu	missense_variant	3/12
FANK1	NM_001363549.2	c.251C>T	p.Pro84Leu	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANK1	ENST00000368693.6	c.269C>T	p.Pro90Leu	missense_variant	3/11	1	NM_145235.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 30, 2024

The c.269C>T (p.P90L) alteration is located in exon 3 (coding exon 3) of the FANK1 gene. This alteration results from a C to T substitution at nucleotide position 269, causing the proline (P) at amino acid position 90 to be replaced by a leucine (L). 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	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;.;T;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.17	T;D;D;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.21	B;.;.;.;.;.
Vest4		0.70
MutPred		0.36		Loss of disorder (P = 0.0279);.;.;.;.;.;
MVP		0.44
MPC		0.34
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr10-127677197;