10-125980285-G-T

Variant names:

• chr10-125980285-G-T
• rs17153882
• NM_145235.5:c.138G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145235.5(FANK1):​c.138G>T​(p.Arg46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.895
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14002627).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANK1	NM_145235.5	MANE Select	c.138G>T	p.Arg46Ser	missense	Exon 2 of 11	NP_660278.3
	FANK1	NM_001350939.2		c.138G>T	p.Arg46Ser	missense	Exon 2 of 12	NP_001337868.1	Q8TC84-3
	FANK1	NM_001363549.2		c.120G>T	p.Arg40Ser	missense	Exon 2 of 11	NP_001350478.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANK1	ENST00000368693.6	TSL:1 MANE Select	c.138G>T	p.Arg46Ser	missense	Exon 2 of 11	ENSP00000357682.1	Q8TC84-1
	FANK1	ENST00000916275.1		c.138G>T	p.Arg46Ser	missense	Exon 2 of 12	ENSP00000586334.1
	FANK1	ENST00000902356.1		c.138G>T	p.Arg46Ser	missense	Exon 2 of 10	ENSP00000572415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.90
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.062
Sift	Benign	0.70	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.20		Loss of helix (P = 0.0068)
MVP		0.24
MPC		0.16
ClinPred		0.11	T
GERP RS		0.76
Varity_R		0.085
gMVP		0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17153882; hg19: chr10-127668854;