11-68903885-T-C

Position:

• chr11-68903885-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000675615(IGHMBP2):​c.-68T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,606,976 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (80 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (76 hom.)
• Consequence: IGHMBP2 ENST00000675615 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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]

(HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 11-68903885-T-C is Benign according to our data. Variant chr11-68903885-T-C is described in ClinVar as [Benign]. Clinvar id is 305827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68903885-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.-68T>C		upstream_gene_variant		ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.-68T>C		upstream_gene_variant		1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2604 AN: 152228 Hom.: 80 Cov.: 34

Gnomad AFR AF: 0.0580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0138

GnomAD4 exome AF: 0.00242 AC: 3524 AN: 1454630 Hom.: 76 Cov.: 33 AF XY: 0.00232 AC XY: 1676 AN XY: 723664

Gnomad4 AFR exome AF: 0.0619

Gnomad4 AMR exome AF: 0.00252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00378

Gnomad4 SAS exome AF: 0.00824

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00588

GnomAD4 genome AF: 0.0171 AC: 2606 AN: 152346 Hom.: 80 Cov.: 34 AF XY: 0.0171 AC XY: 1271 AN XY: 74518

Gnomad4 AFR AF: 0.0579

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00598

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0147 Hom.: 3

Bravo AF: 0.0196

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive distal spinal muscular atrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.7
DANN	Benign	0.50

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: rs57258566; hg19: chr11-68671353;