1-8013444-A-C

Variant names:

• chr1-8013444-A-C
• rs1369574916
• NM_018948.4:c.1155T>G

Variant summary

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

The NM_018948.4(ERRFI1):​c.1155T>G​(p.Asn385Lys) 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 1,461,894 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: 6.8e-7 (0 hom.)
• Consequence: ERRFI1 NM_018948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0450

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.1155T>G	p.Asn385Lys	missense_variant	Exon 4 of 4	ENST00000377482.10	NP_061821.1
ERRFI1	XM_047422698.1	c.1155T>G	p.Asn385Lys	missense_variant	Exon 3 of 3		XP_047278654.1
ERRFI1	XM_005263477.4	c.1002T>G	p.Asn334Lys	missense_variant	Exon 3 of 3		XP_005263534.1
ERRFI1	XM_047422701.1	c.930T>G	p.Asn310Lys	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.1155T>G	p.Asn385Lys	missense_variant	Exon 4 of 4	1	NM_018948.4	ENSP00000366702.5
ERRFI1	ENST00000467067	c.*1826T>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000465100.1
ERRFI1	ENST00000474874.5	c.125+2051T>G		intron_variant	Intron 2 of 2	3		ENSP00000466958.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1155T>G (p.N385K) alteration is located in exon 4 (coding exon 3) of the ERRFI1 gene. This alteration results from a T to G substitution at nucleotide position 1155, causing the asparagine (N) at amino acid position 385 to be replaced by a lysine (K). 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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		0.95	P
Vest4		0.59
MutPred		0.52		Gain of methylation at N385 (P = 0.0019);
MVP		0.48
MPC		0.49
ClinPred		0.99	D
GERP RS		-8.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.34

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: rs1369574916; hg19: chr1-8073504;