19-41908427-C-G

Variant names:

• chr19-41908427-C-G
• rs138952382
• NM_001365103.2:c.866G>C

Variant summary

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

The NM_001365103.2(ERFL):​c.866G>C​(p.Arg289Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,079,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/7 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. R289H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: ERFL NM_001365103.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 0 publications found

Genes affected

ERFL (HGNC:53894): (ETS repressor factor like) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF1 (HGNC:681): (Rho guanine nucleotide exchange factor 1) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ARHGEF1 Gene-Disease associations (from GenCC):

• immunodeficiency 62

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

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=0.11819592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365103.2. 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
	ERFL	NM_001365103.2	MANE Select	c.866G>C	p.Arg289Pro	missense	Exon 6 of 6	NP_001352032.1	A0A1W2PQ73
	ARHGEF1	NM_001396003.1		c.2592+1624C>G		intron	N/A	NP_001382932.1
	ARHGEF1	NM_001396002.1		c.2493+1624C>G		intron	N/A	NP_001382931.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERFL	ENST00000597630.3	TSL:5 MANE Select	c.866G>C	p.Arg289Pro	missense	Exon 6 of 6	ENSP00000491574.1	A0A1W2PQ73
	ARHGEF1	ENST00000599589.5	TSL:1	c.1863+1624C>G		intron	N/A	ENSP00000469735.1	M0QYC1
	ARHGEF1	ENST00000698932.1		c.2592+1624C>G		intron	N/A	ENSP00000514042.1	A0A8V8TP90

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.27e-7 AC: 1 AN: 1079002 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 509360

African (AFR) AF: 0.00 AC: 0 AN: 22946

American (AMR) AF: 0.00 AC: 0 AN: 8400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14364

East Asian (EAS) AF: 0.00 AC: 0 AN: 26508

South Asian (SAS) AF: 0.00 AC: 0 AN: 19488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2914

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 919650

Other (OTH) AF: 0.00 AC: 0 AN: 43632

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.70
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.12	T
PhyloP100		-0.39
GERP RS		0.68

Splicing

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

Other links and lift over

dbSNP: rs138952382; hg19: chr19-42412579;