NM_001365103.2:c.708G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001365103.2(ERFL):​c.708G>A​(p.Thr236Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,231,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T236T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ERFL NM_001365103.2 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=-0.991 with no splicing effect.

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>A	p.Thr236Thr	synonymous	Exon 6 of 6	NP_001352032.1	A0A1W2PQ73
	ARHGEF1	NM_001396003.1		c.2592+1782C>T		intron	N/A	NP_001382932.1
	ARHGEF1	NM_001396002.1		c.2493+1782C>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.708G>A	p.Thr236Thr	synonymous	Exon 6 of 6	ENSP00000491574.1	A0A1W2PQ73
	ARHGEF1	ENST00000599589.5	TSL:1	c.1863+1782C>T		intron	N/A	ENSP00000469735.1	M0QYC1
	ARHGEF1	ENST00000698932.1		c.2592+1782C>T		intron	N/A	ENSP00000514042.1	A0A8V8TP90

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000834 AC: 9 AN: 1079698 Hom.: 0 Cov.: 32 AF XY: 0.00000981 AC XY: 5 AN XY: 509732

African (AFR) AF: 0.00 AC: 0 AN: 22970

American (AMR) AF: 0.00 AC: 0 AN: 8418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14396

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 19504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2918

European-Non Finnish (NFE) AF: 0.00000978 AC: 9 AN: 920168

Other (OTH) AF: 0.00 AC: 0 AN: 43680

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74156

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000531 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.024
DANN	Benign	0.87
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;