chr5-112184037-C-T

Variant names:

• chr5-112184037-C-T
• rs545808705
• NM_022140.5:c.1601G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022140.5(EPB41L4A):​c.1601G>A​(p.Arg534Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPB41L4A NM_022140.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022140.5. 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
	EPB41L4A	NM_022140.5	MANE Select	c.1601G>A	p.Arg534Gln	missense	Exon 18 of 23	NP_071423.4
	EPB41L4A	NM_001347887.2		c.1601G>A	p.Arg534Gln	missense	Exon 18 of 24	NP_001334816.1
	EPB41L4A	NR_144931.2		n.1839G>A		non_coding_transcript_exon	Exon 18 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41L4A	ENST00000261486.6	TSL:1 MANE Select	c.1601G>A	p.Arg534Gln	missense	Exon 18 of 23	ENSP00000261486.5	Q9HCS5
	EPB41L4A	ENST00000507810.5	TSL:2	n.621G>A		non_coding_transcript_exon	Exon 7 of 14
	EPB41L4A	ENST00000515047.5	TSL:3	n.421G>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249542 AF XY: 0.00

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.010	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.9	L
PhyloP100		6.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.10	T
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.94
MPC		0.26
ClinPred		0.78	D
GERP RS		6.2
Varity_R		0.19
gMVP		0.53
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs545808705; hg19: chr5-111519734; COSMIC: COSV105051481; COSMIC: COSV105051481;