5-112204453-G-A

Variant names:

• chr5-112204453-G-A
• rs730882207
• NM_022140.5:c.1298C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_022140.5(EPB41L4A):​c.1298C>T​(p.Ser433Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EPB41L4A NM_022140.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.01

Genes affected

EPB41L4A (HGNC:13278): (erythrocyte membrane protein band 4.1 like 4A) The protein encoded by this gene is a member of the band 4.1 protein superfamily. Members of this superfamily are thought to play an important role in regulating interactions between the cytoskeleton and plasma membrane, and contain an amino terminal conserved domain that binds glycophorin C. This gene product is thought to be involved in the beta-catenin signaling pathway. [provided by RefSeq, Dec 2016]

ENSG00000251187 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 5-112204453-G-A is Pathogenic according to our data. Variant chr5-112204453-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183292.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-112204453-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-112204453-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41L4A	NM_022140.5	c.1298C>T	p.Ser433Leu	missense_variant	Exon 15 of 23	ENST00000261486.6	NP_071423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41L4A	ENST00000261486.6	c.1298C>T	p.Ser433Leu	missense_variant	Exon 15 of 23	1	NM_022140.5	ENSP00000261486.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249572 AF XY: 0.00000739

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461436 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000598 AC: 2 AN: 33468

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44722

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26124

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86244

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53382

Gnomad4 NFE exome AF: 0.0000117 AC: 13 AN: 1111662

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.0000482 AC: 0.0000481812 AN: 0.0000481812

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000193424 AN: 0.000193424

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147042 AN: 0.0000147042

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spastic paraplegia;C2315100:Failure to thrive Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.82
MVP		0.95
MPC		0.29
ClinPred		0.78	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.57
Mutation Taster		=27/73	disease causing (ClinVar)

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: rs730882207; hg19: chr5-111540150; COSMIC: COSV54862790;