9-109176554-G-A

Variant names:

• chr9-109176554-G-A
• rs201310807
• NM_019114.5:c.2630C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_019114.5(EPB41L4B):​c.2630C>T​(p.Ala877Val) variant causes a missense change. The variant allele was found at a frequency of 0.000725 in 1,605,702 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (5 hom.)
• Consequence: EPB41L4B NM_019114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.00

Genes affected

EPB41L4B (HGNC:19818): (erythrocyte membrane protein band 4.1 like 4B) Predicted to be a structural constituent of cytoskeleton. Involved in several processes, including positive regulation of cell adhesion; positive regulation of keratinocyte migration; and wound healing. Acts upstream of or within actomyosin structure organization. Located in apical part of cell; cytosol; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0120204985).
• BP6: Variant 9-109176554-G-A is Benign according to our data. Variant chr9-109176554-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2353008.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L4B	NM_019114.5	c.2630C>T	p.Ala877Val	missense_variant	Exon 25 of 26	ENST00000374566.8	NP_061987.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L4B	ENST00000374566.8	c.2630C>T	p.Ala877Val	missense_variant	Exon 25 of 26	1	NM_019114.5	ENSP00000363694.3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000817 AC: 199 AN: 243644 Hom.: 2 AF XY: 0.000998 AC XY: 132 AN XY: 132298

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.000618

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00149

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000717 AC: 1042 AN: 1453418 Hom.: 5 Cov.: 30 AF XY: 0.000738 AC XY: 533 AN XY: 722188

Gnomad4 AFR exome AF: 0.0000905

Gnomad4 AMR exome AF: 0.000956

Gnomad4 ASJ exome AF: 0.000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000721

Gnomad4 OTH exome AF: 0.000750

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000739 AC XY: 55 AN XY: 74446

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.000786 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2630C>T (p.A877V) alteration is located in exon 25 (coding exon 25) of the EPB41L4B gene. This alteration results from a C to T substitution at nucleotide position 2630, causing the alanine (A) at amino acid position 877 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPB41L4B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.25	T
Polyphen		0.10	B
Vest4		0.17
MVP		0.40
MPC		0.25
ClinPred		0.041	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs201310807; hg19: chr9-111938834;