8-123973492-G-A

Position:

• chr8-123973492-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001039112.2(FER1L6):​c.506G>A​(p.Gly169Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: FER1L6 NM_001039112.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.71

Genes affected

FER1L6 (HGNC:28065): (fer-1 like family member 6) Predicted to enable metal ion binding activity. Predicted to be involved in plasma membrane organization. Predicted to act upstream of or within response to bacterium. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FER1L6	NM_001039112.2	c.506G>A	p.Gly169Glu	missense_variant	7/41	ENST00000522917.5	NP_001034201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FER1L6	ENST00000522917.5	c.506G>A	p.Gly169Glu	missense_variant	7/41	1	NM_001039112.2	ENSP00000428280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461696 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

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: 0.0000166

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

Mar 19, 2024

The c.506G>A (p.G169E) alteration is located in exon 6 (coding exon 6) of the FER1L6 gene. This alteration results from a G to A substitution at nucleotide position 506, causing the glycine (G) at amino acid position 169 to be replaced by a glutamic acid (E). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.81		Gain of ubiquitination at K165 (P = 0.0683);
MVP		0.53
MPC		0.60
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.47
gMVP		0.74

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: rs1586538427; hg19: chr8-124985732;