Genetic Variant IGHMBP2:c.-34C>G (chr11-68903919-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002180.3(IGHMBP2):c.-34C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,599,662 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

IGHMBP2
NM_002180.3 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.97

Publications

0 publications found

Variant links:

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 links:

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

MRPL21 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BP6

Variant 11-68903919-C-G is Benign according to our data. Variant chr11-68903919-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 388783.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (175/152334) while in subpopulation AFR AF = 0.00409 (170/41552). AF 95% confidence interval is 0.00359. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGHMBP2	NM_002180.3	MANE Select	c.-34C>G	5_prime_UTR	Exon 1 of 15	NP_002171.2	P38935
MRPL21	NM_181514.2	MANE Select	c.-109G>C	upstream_gene	N/A	NP_852615.1	Q7Z2W9-1
MRPL21	NM_181515.2		c.-377G>C	upstream_gene	N/A	NP_852616.1	Q7Z2W9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.-34C>G	5_prime_UTR	Exon 1 of 15	ENSP00000255078.4	P38935
IGHMBP2	ENST00000925063.1		c.-34C>G	5_prime_UTR	Exon 1 of 14	ENSP00000595122.1
IGHMBP2	ENST00000675615.1		c.-34C>G	5_prime_UTR	Exon 1 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000271

AC:

AN:

217544

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.00414

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

179

AN:

1447328

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

719156

show subpopulations

African (AFR)

AF:

0.00402

AC:

133

AN:

33104

American (AMR)

AF:

0.000187

AC:

AN:

42774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00

AC:

AN:

39232

South Asian (SAS)

AF:

0.0000706

AC:

AN:

84966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

1104570

Other (OTH)

AF:

0.000234

AC:

AN:

59778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152334

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00409

AC:

170

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000695

Hom.:

Bravo

AF:

0.00129

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

4.3

(source)

DANN

Benign

0.49

PhyloP100

-2.0

PromoterAI

-0.060

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over