NM_001365103.2:c.708G>C

Variant names:

• chr19-41908585-C-G
• rs541109321
• NM_001365103.2:c.708G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001365103.2(ERFL):​c.708G>C​(p.Thr236Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,231,698 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (7 hom.)
• Consequence: ERFL NM_001365103.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.991
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-41908585-C-G is Benign according to our data. Variant chr19-41908585-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3770835.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.991 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 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.708G>C	p.Thr236Thr	synonymous	Exon 6 of 6	NP_001352032.1	A0A1W2PQ73
	ARHGEF1	NM_001396003.1		c.2592+1782C>G		intron	N/A	NP_001382932.1
	ARHGEF1	NM_001396002.1		c.2493+1782C>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.708G>C	p.Thr236Thr	synonymous	Exon 6 of 6	ENSP00000491574.1	A0A1W2PQ73
	ARHGEF1	ENST00000599589.5	TSL:1	c.1863+1782C>G		intron	N/A	ENSP00000469735.1	M0QYC1
	ARHGEF1	ENST00000698932.1		c.2592+1782C>G		intron	N/A	ENSP00000514042.1	A0A8V8TP90

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 151882 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.00358 AC: 3866 AN: 1079698 Hom.: 7 Cov.: 32 AF XY: 0.00359 AC XY: 1832 AN XY: 509732

African (AFR) AF: 0.000479 AC: 11 AN: 22970

American (AMR) AF: 0.00143 AC: 12 AN: 8418

Ashkenazi Jewish (ASJ) AF: 0.0000695 AC: 1 AN: 14396

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

South Asian (SAS) AF: 0.000359 AC: 7 AN: 19504

European-Finnish (FIN) AF: 0.000995 AC: 21 AN: 21116

Middle Eastern (MID) AF: 0.000685 AC: 2 AN: 2918

European-Non Finnish (NFE) AF: 0.00404 AC: 3714 AN: 920168

Other (OTH) AF: 0.00224 AC: 98 AN: 43680

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152000 Hom.: 2 Cov.: 31 AF XY: 0.00205 AC XY: 152 AN XY: 74284

African (AFR) AF: 0.000579 AC: 24 AN: 41450

American (AMR) AF: 0.000720 AC: 11 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00442 AC: 300 AN: 67902

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00208

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0070
DANN	Benign	0.71
PhyloP100		-0.99

Splicing

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

Other links and lift over

dbSNP: rs541109321; hg19: chr19-42412737;