19-41908427-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 3341602.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 32 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERFL	NM_001365103.2	c.866G>A	p.Arg289His	missense_variant	Exon 6 of 6	ENST00000597630.3	NP_001352032.1
ARHGEF1	NM_001396003.1	c.2592+1624C>T		intron_variant	Intron 27 of 28		NP_001382932.1
ARHGEF1	NM_001396002.1	c.2493+1624C>T		intron_variant	Intron 26 of 27		NP_001382931.1
ARHGEF1	NR_173092.1	n.4253+1624C>T		intron_variant	Intron 29 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERFL	ENST00000597630.3	c.866G>A	p.Arg289His	missense_variant	Exon 6 of 6	5	NM_001365103.2	ENSP00000491574.1
ARHGEF1	ENST00000599589.5	c.1863+1624C>T		intron_variant	Intron 18 of 20	1		ENSP00000469735.1
ARHGEF1	ENST00000698932.1	c.2592+1624C>T		intron_variant	Intron 27 of 28			ENSP00000514042.1
ARHGEF1	ENST00000698934.1	n.*17+1624C>T		intron_variant	Intron 29 of 30			ENSP00000514044.1

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

Gnomad4 AFR exome AF: 0.00205

Gnomad4 AMR exome AF: 0.00679

Gnomad4 ASJ exome AF: 0.00118

Gnomad4 EAS exome AF: 0.000226

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.0362

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0107

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

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000971

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00899

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERFL: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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
GERP RS		0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138952382; hg19: chr19-42412579;