5-65992762-G-T

Variant names:

• chr5-65992762-G-T
• rs949907598
• NM_001253697.2:c.44G>T

Variant summary

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

The NM_001253697.2(ERBIN):​c.44G>T​(p.Arg15Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERBIN NM_001253697.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.89
• Publications: 0 publications found

Genes affected

ERBIN (HGNC:15842): (erbb2 interacting protein) This gene is a member of the leucine-rich repeat and PDZ domain (LAP) family. The encoded protein contains 17 leucine-rich repeats and one PDZ domain. It binds to the unphosphorylated form of the ERBB2 protein and regulates ERBB2 function and localization. It has also been shown to affect the Ras signaling pathway by disrupting Ras-Raf interaction. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ERBIN Gene-Disease associations (from GenCC):

• autosomal dominant combined immunodeficiency due to ERBIN deficiency

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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_001253697.2. 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
	ERBIN	NM_001253697.2	MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 3 of 26	NP_001240626.1	Q96RT1-1
	ERBIN	NM_001253699.2		c.44G>T	p.Arg15Leu	missense	Exon 3 of 26	NP_001240628.1	Q96RT1-8
	ERBIN	NM_018695.4		c.44G>T	p.Arg15Leu	missense	Exon 3 of 25	NP_061165.1	Q96RT1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBIN	ENST00000284037.10	TSL:1 MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 3 of 26	ENSP00000284037.4	Q96RT1-1
	ERBIN	ENST00000506030.6	TSL:1	c.44G>T	p.Arg15Leu	missense	Exon 3 of 26	ENSP00000426632.1	Q96RT1-8
	ERBIN	ENST00000380943.6	TSL:1	c.44G>T	p.Arg15Leu	missense	Exon 3 of 25	ENSP00000370330.2	Q96RT1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460240 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111366

Other (OTH) AF: 0.00 AC: 0 AN: 60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.61	T
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.47		Loss of MoRF binding (P = 0.0309)
MVP		0.28
MPC		0.45
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.61
Mutation Taster		=21/79	disease causing

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: rs949907598; hg19: chr5-65288590;