NM_001365103.2:c.866G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365103.2(ERFL):​c.866G>A​(p.Arg289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,231,180 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 32)
  • Exomes 𝑓: 0.014 (122 hom.)
• Consequence: ERFL NM_001365103.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054450035).
• BP6: Variant 19-41908427-C-T is Benign according to our data. Variant chr19-41908427-C-T is described in ClinVar as Benign. ClinVar VariationId is 3341602.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 32 gene

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>A	p.Arg289His	missense	Exon 6 of 6	NP_001352032.1	A0A1W2PQ73
	ARHGEF1	NM_001396003.1		c.2592+1624C>T		intron	N/A	NP_001382932.1
	ARHGEF1	NM_001396002.1		c.2493+1624C>T		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>A	p.Arg289His	missense	Exon 6 of 6	ENSP00000491574.1	A0A1W2PQ73
	ARHGEF1	ENST00000599589.5	TSL:1	c.1863+1624C>T		intron	N/A	ENSP00000469735.1	M0QYC1
	ARHGEF1	ENST00000698932.1		c.2592+1624C>T		intron	N/A	ENSP00000514042.1	A0A8V8TP90

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1720 AN: 152064 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.0137 AC: 14834 AN: 1078998 Hom.: 122 Cov.: 31 AF XY: 0.0135 AC XY: 6901 AN XY: 509360

African (AFR) AF: 0.00205 AC: 47 AN: 22946

American (AMR) AF: 0.00679 AC: 57 AN: 8400

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 17 AN: 14364

East Asian (EAS) AF: 0.000226 AC: 6 AN: 26508

South Asian (SAS) AF: 0.00313 AC: 61 AN: 19488

European-Finnish (FIN) AF: 0.0362 AC: 763 AN: 21100

Middle Eastern (MID) AF: 0.000686 AC: 2 AN: 2914

European-Non Finnish (NFE) AF: 0.0146 AC: 13416 AN: 919646

Other (OTH) AF: 0.0107 AC: 465 AN: 43632

GnomAD4 genome AF: 0.0113 AC: 1719 AN: 152182 Hom.: 32 Cov.: 32 AF XY: 0.0122 AC XY: 910 AN XY: 74394

African (AFR) AF: 0.00221 AC: 92 AN: 41536

American (AMR) AF: 0.00608 AC: 93 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000971 AC: 5 AN: 5148

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0452 AC: 479 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1001 AN: 67974

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0117 Hom.: 1

Bravo AF: 0.00826

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0117 AC: 45

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.85
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0054	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;