19-41908628-C-T

Variant names:

• chr19-41908628-C-T
• rs189773033
• NM_001365103.2:c.665G>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.665G>A​(p.Arg222His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,231,550 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (49 hom.)
• Consequence: ERFL NM_001365103.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20
• 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=0.009852201).
• BP6: Variant 19-41908628-C-T is Benign according to our data. Variant chr19-41908628-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3341626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 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.665G>A	p.Arg222His	missense	Exon 6 of 6	NP_001352032.1	A0A1W2PQ73
	ARHGEF1	NM_001396003.1		c.2592+1825C>T		intron	N/A	NP_001382932.1
	ARHGEF1	NM_001396002.1		c.2493+1825C>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.665G>A	p.Arg222His	missense	Exon 6 of 6	ENSP00000491574.1	A0A1W2PQ73
	ARHGEF1	ENST00000599589.5	TSL:1	c.1863+1825C>T		intron	N/A	ENSP00000469735.1	M0QYC1
	ARHGEF1	ENST00000698932.1		c.2592+1825C>T		intron	N/A	ENSP00000514042.1	A0A8V8TP90

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 943 AN: 151828 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00825

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00774 AC: 8353 AN: 1079604 Hom.: 49 Cov.: 32 AF XY: 0.00768 AC XY: 3916 AN XY: 509664

African (AFR) AF: 0.00118 AC: 27 AN: 22970

American (AMR) AF: 0.00333 AC: 28 AN: 8418

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 15 AN: 14392

East Asian (EAS) AF: 0.00 AC: 0 AN: 26528

South Asian (SAS) AF: 0.000103 AC: 2 AN: 19498

European-Finnish (FIN) AF: 0.0175 AC: 370 AN: 21116

Middle Eastern (MID) AF: 0.00137 AC: 4 AN: 2918

European-Non Finnish (NFE) AF: 0.00838 AC: 7709 AN: 920086

Other (OTH) AF: 0.00453 AC: 198 AN: 43678

GnomAD4 genome AF: 0.00620 AC: 942 AN: 151946 Hom.: 4 Cov.: 31 AF XY: 0.00668 AC XY: 496 AN XY: 74240

African (AFR) AF: 0.00150 AC: 62 AN: 41424

American (AMR) AF: 0.00766 AC: 117 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00825 AC: 560 AN: 67890

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00625 Hom.: 0

Bravo AF: 0.00519

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00727 AC: 28

ClinVar

ClinVar submissions

Significance: Likely 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	0.13
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.91
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0099	T
PhyloP100		1.2
GERP RS		3.0

Splicing

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

Other links and lift over

dbSNP: rs189773033; hg19: chr19-42412780;