10-125980285-G-C

Position:

• chr10-125980285-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_145235.5(FANK1):​c.138G>C​(p.Arg46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,614,014 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (79 hom., cov: 32)
  • Exomes 𝑓: 0.031 (838 hom.)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.895

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00315395).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0235 (3575/152154) while in subpopulation NFE AF= 0.0331 (2247/67968). AF 95% confidence interval is 0.0319. There are 79 homozygotes in gnomad4. There are 1684 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANK1	NM_145235.5	c.138G>C	p.Arg46Ser	missense_variant	2/11	ENST00000368693.6	NP_660278.3
FANK1	NM_001350939.2	c.138G>C	p.Arg46Ser	missense_variant	2/12		NP_001337868.1
FANK1	NM_001363549.2	c.120G>C	p.Arg40Ser	missense_variant	2/11		NP_001350478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANK1	ENST00000368693.6	c.138G>C	p.Arg46Ser	missense_variant	2/11	1	NM_145235.5	ENSP00000357682	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3582 AN: 152036 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0242 AC: 6094 AN: 251410 Hom.: 112 AF XY: 0.0244 AC XY: 3313 AN XY: 135874

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00840

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0351

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0308 AC: 45092 AN: 1461860 Hom.: 838 Cov.: 31 AF XY: 0.0303 AC XY: 22058 AN XY: 727226

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00830

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0352

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0235 AC: 3575 AN: 152154 Hom.: 79 Cov.: 32 AF XY: 0.0226 AC XY: 1684 AN XY: 74392

Gnomad4 AFR AF: 0.00660

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0320 Hom.: 63

Bravo AF: 0.0239

TwinsUK AF: 0.0356 AC: 132

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0240 AC: 2914

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0342

EpiControl AF: 0.0369

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T;T;.;T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.71	T;T;T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.70	T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.11
MutPred		0.20		Loss of helix (P = 0.0068);.;.;.;.;.;
MPC		0.16
ClinPred		0.0094	T
GERP RS		0.76
Varity_R		0.085
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs17153882; hg19: chr10-127668854;