rs140221316

Variant names:

• chr11-68934529-A-G
• rs140221316
• NM_002180.3:c.1603A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_002180.3(IGHMBP2):​c.1603A>G​(p.Ile535Val) variant causes a missense change. The variant allele was found at a frequency of 0.000295 in 1,612,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I535M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 4.96
• Publications: 3 publications found

Genes affected

IGHMBP2 (HGNC:5542): (immunoglobulin mu DNA binding protein 2) This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

IGHMBP2 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002180.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.018820047).
• BP6: Variant 11-68934529-A-G is Benign according to our data. Variant chr11-68934529-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432239.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (187/152284) while in subpopulation AFR AF = 0.00431 (179/41546). AF 95% confidence interval is 0.00379. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. 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
	IGHMBP2	NM_002180.3	MANE Select	c.1603A>G	p.Ile535Val	missense	Exon 11 of 15	NP_002171.2	P38935

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.1603A>G	p.Ile535Val	missense	Exon 11 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000541229.5	TSL:1	n.298A>G		non_coding_transcript_exon	Exon 2 of 4
	IGHMBP2	ENST00000925063.1		c.1420A>G	p.Ile474Val	missense	Exon 10 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000376 AC: 93 AN: 247652 AF XY: 0.000239

Gnomad AFR exome AF: 0.00485

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1460592 Hom.: 1 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 726428

African (AFR) AF: 0.00553 AC: 185 AN: 33442

American (AMR) AF: 0.000179 AC: 8 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

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

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1111394

Other (OTH) AF: 0.000265 AC: 16 AN: 60350

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74460

African (AFR) AF: 0.00431 AC: 179 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000952 Hom.: 3

Bravo AF: 0.00153

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	9.9
DANN	Benign	0.59
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.36	B
Vest4		0.25
MVP		0.80
MPC		0.25
ClinPred		0.026	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.55
Mutation Taster		=79/21	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: rs140221316; hg19: chr11-68701997;