NM_001376013.1:c.33C>G

Variant names:

• chr1-28987470-C-G
• rs142705709
• NM_001376013.1:c.33C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_001376013.1(EPB41):​c.33C>G​(p.Ala11Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: EPB41 NM_001376013.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14
• Publications: 1 publications found

Genes affected

EPB41 (HGNC:3377): (erythrocyte membrane protein band 4.1) The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Oct 2009]

EPB41 Gene-Disease associations (from GenCC):

• elliptocytosis 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-28987470-C-G is Benign according to our data. Variant chr1-28987470-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2638582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000158 (24/152080) while in subpopulation NFE AF = 0.000309 (21/67994). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376013.1. 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
	EPB41	NM_001376013.1	MANE Select	c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 21	NP_001362942.1	P11171-1
	EPB41	NM_001166005.2		c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 21	NP_001159477.1	P11171-1
	EPB41	NM_001376014.1		c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 20	NP_001362943.1	A0A2U3TZH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41	ENST00000343067.9	TSL:5 MANE Select	c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 21	ENSP00000345259.4	P11171-1
	EPB41	ENST00000349460.9	TSL:1	c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 20	ENSP00000317597.8	A0A2U3TZH6
	EPB41	ENST00000347529.7	TSL:1	c.33C>G	p.Ala11Ala	synonymous	Exon 2 of 17	ENSP00000290100.6	P11171-5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251252 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461876 Hom.: 1 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 727236

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111998

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000276 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-2.1
Mutation Taster		=294/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142705709; hg19: chr1-29313982;