8-124017699-C-A

Variant names:

• chr8-124017699-C-A
• rs367553708
• NM_001039112.2:c.1994C>A

Variant summary

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

The NM_001039112.2(FER1L6):​c.1994C>A​(p.Thr665Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T665R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FER1L6 NM_001039112.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 2 publications found

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]

FER1L6-AS1 (HGNC:26652): (FER1L6 antisense RNA 1)

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=0.10521689).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039112.2. 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
	FER1L6	NM_001039112.2	MANE Select	c.1994C>A	p.Thr665Lys	missense	Exon 16 of 41	NP_001034201.2	Q2WGJ9
	FER1L6-AS1	NR_040044.1		n.158-1657G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FER1L6	ENST00000522917.5	TSL:1 MANE Select	c.1994C>A	p.Thr665Lys	missense	Exon 16 of 41	ENSP00000428280.1	Q2WGJ9
	FER1L6-AS1	ENST00000518567.1	TSL:2	n.158-1657G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249266 AF XY: 0.00000740

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461164 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726886

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

African (AFR) AF: 0.0000598 AC: 2 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111466

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.5	N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.70	P
Vest4		0.30
MutPred		0.35		Gain of MoRF binding (P = 0.0177)
MVP		0.29
MPC		0.15
ClinPred		0.30	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.30
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367553708; hg19: chr8-125029939; COSMIC: COSV67550122;