1-8013566-C-A

Variant names:

• chr1-8013566-C-A
• rs1310945323
• NM_018948.4:c.1033G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018948.4(ERRFI1):​c.1033G>T​(p.Val345Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ERRFI1 NM_018948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

Genes affected

ERRFI1 (HGNC:18185): (ERBB receptor feedback inhibitor 1) ERRFI1 is a cytoplasmic protein whose expression is upregulated with cell growth (Wick et al., 1995 [PubMed 7641805]). It shares significant homology with the protein product of rat gene-33, which is induced during cell stress and mediates cell signaling (Makkinje et al., 2000 [PubMed 10749885]; Fiorentino et al., 2000 [PubMed 11003669]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERRFI1	NM_018948.4	c.1033G>T	p.Val345Phe	missense_variant	Exon 4 of 4	ENST00000377482.10	NP_061821.1
ERRFI1	XM_047422698.1	c.1033G>T	p.Val345Phe	missense_variant	Exon 3 of 3		XP_047278654.1
ERRFI1	XM_005263477.4	c.880G>T	p.Val294Phe	missense_variant	Exon 3 of 3		XP_005263534.1
ERRFI1	XM_047422701.1	c.808G>T	p.Val270Phe	missense_variant	Exon 2 of 2		XP_047278657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERRFI1	ENST00000377482.10	c.1033G>T	p.Val345Phe	missense_variant	Exon 4 of 4	1	NM_018948.4	ENSP00000366702.5
ERRFI1	ENST00000467067	c.*1704G>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000465100.1
ERRFI1	ENST00000474874.5	c.125+1929G>T		intron_variant	Intron 2 of 2	3		ENSP00000466958.1
ERRFI1	ENST00000469499.5	c.*731G>T		downstream_gene_variant		3		ENSP00000466454.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1033G>T (p.V345F) alteration is located in exon 4 (coding exon 3) of the ERRFI1 gene. This alteration results from a G to T substitution at nucleotide position 1033, causing the valine (V) at amino acid position 345 to be replaced by a phenylalanine (F). 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	0.56
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.11		Loss of catalytic residue at V345 (P = 0.0852);
MVP		0.89
MPC		0.83
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.51

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: rs1310945323; hg19: chr1-8073626;