rs140731421

Variant names:

• chr20-36173888-C-T
• rs140731421
• NM_012156.2:c.111C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_012156.2(EPB41L1):​c.111C>T​(p.His37His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,974 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: EPB41L1 NM_012156.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.919
• Publications: 1 publications found

Genes affected

EPB41L1 (HGNC:3378): (erythrocyte membrane protein band 4.1 like 1) Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

EPB41L1 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• intellectual disability, autosomal dominant 11

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 20-36173888-C-T is Benign according to our data. Variant chr20-36173888-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 736255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.919 with no splicing effect.
• BS2: High AC in GnomAd4 at 150 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012156.2. 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
	EPB41L1	NM_012156.2	MANE Select	c.111C>T	p.His37His	synonymous	Exon 2 of 22	NP_036288.2	Q9H4G0-1
	EPB41L1	NM_001433605.1		c.111C>T	p.His37His	synonymous	Exon 2 of 23	NP_001420534.1
	EPB41L1	NM_001258329.1		c.111C>T	p.His37His	synonymous	Exon 3 of 23	NP_001245258.1	A0A0C4DH22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L1	ENST00000338074.7	TSL:1 MANE Select	c.111C>T	p.His37His	synonymous	Exon 2 of 22	ENSP00000337168.2	Q9H4G0-1
	EPB41L1	ENST00000373946.7	TSL:1	c.111C>T	p.His37His	synonymous	Exon 3 of 23	ENSP00000363057.4	A0A0C4DH22
	EPB41L1	ENST00000202028.9	TSL:1	c.-9-1663C>T		intron	N/A	ENSP00000202028.5	Q9H4G0-2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000880 AC: 220 AN: 250042 AF XY: 0.000879

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00175 AC: 2559 AN: 1461690 Hom.: 5 Cov.: 32 AF XY: 0.00173 AC XY: 1256 AN XY: 727164

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00208 AC: 2315 AN: 1111906

Other (OTH) AF: 0.00359 AC: 217 AN: 60386

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74450

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.000929

EpiCase AF: 0.00180

EpiControl AF: 0.000653

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.92
PromoterAI		0.017	Neutral
Mutation Taster		=99/1	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: rs140731421; hg19: chr20-34761810; COSMIC: COSV52434417;