10-126009428-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_145235.5(FANK1):c.1028G>T(p.Cys343Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,614,116 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (49 hom.)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.404

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004339367).
• BP6: Variant 10-126009428-G-T is Benign according to our data. Variant chr10-126009428-G-T is described in ClinVar as [Benign]. Clinvar id is 773521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANK1	NM_145235.5	c.1028G>T	p.Cys343Phe	missense_variant	11/11	ENST00000368693.6
FANK1	NM_001350939.2	c.1106G>T	p.Cys369Phe	missense_variant	12/12
FANK1	NM_001363549.2	c.1010G>T	p.Cys337Phe	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANK1	ENST00000368693.6	c.1028G>T	p.Cys343Phe	missense_variant	11/11	1	NM_145235.5	P1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 731 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00766

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00522 AC: 1311 AN: 251324 Hom.: 10 AF XY: 0.00526 AC XY: 714 AN XY: 135822

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00578

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.00678

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00442 AC: 6466 AN: 1461858 Hom.: 49 Cov.: 32 AF XY: 0.00467 AC XY: 3399 AN XY: 727220

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00664

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00439

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74468

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00766

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00592 Hom.: 10

Bravo AF: 0.00320

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00548 AC: 665

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	5.6
Dann	Benign	0.86
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.059	T;T;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.0020	B;.;.
Vest4		0.10
MVP		0.28
MPC		0.22
ClinPred		0.0042	T
GERP RS		3.1
Varity_R		0.086
gMVP		0.18

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

Other links and lift over

dbSNP: rs17153976; hg19: chr10-127697997;