NM_032380.5:c.2211+122_2211+126dupAAGTT

Variant names:

• chr5-74722252-A-AAACTT
• rs70976129
• NM_032380.5:c.2211+122_2211+126dupAAGTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_032380.5(GFM2):​c.2211+122_2211+126dupAAGTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 804,588 control chromosomes in the GnomAD database, including 503 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (78 hom., cov: 32)
  • Exomes 𝑓: 0.031 (425 hom.)
• Consequence: GFM2 NM_032380.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.315
• Publications: 0 publications found

Genes affected

GFM2 (HGNC:29682): (GTP dependent ribosome recycling factor mitochondrial 2) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

HEXB Gene-Disease associations (from GenCC):

• Sandhoff disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-74722252-A-AAACTT is Benign according to our data. Variant chr5-74722252-A-AAACTT is described in ClinVar as [Benign]. Clinvar id is 1179243.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0268 (4077/152300) while in subpopulation NFE AF = 0.037 (2517/68028). AF 95% confidence interval is 0.0358. There are 78 homozygotes in GnomAd4. There are 2024 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM2	NM_032380.5	c.2211+122_2211+126dupAAGTT		intron_variant	Intron 20 of 20	ENST00000296805.8	NP_115756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM2	ENST00000296805.8	c.2211+126_2211+127insAAGTT		intron_variant	Intron 20 of 20	1	NM_032380.5	ENSP00000296805.3

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4078 AN: 152182 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0210

GnomAD4 exome AF: 0.0310 AC: 20245 AN: 652288 Hom.: 425 Cov.: 9 AF XY: 0.0311 AC XY: 10536 AN XY: 338380

African (AFR) AF: 0.00593 AC: 99 AN: 16706

American (AMR) AF: 0.0115 AC: 267 AN: 23164

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 621 AN: 15304

East Asian (EAS) AF: 0.0000867 AC: 3 AN: 34594

South Asian (SAS) AF: 0.0332 AC: 1695 AN: 51018

European-Finnish (FIN) AF: 0.0574 AC: 1953 AN: 34026

Middle Eastern (MID) AF: 0.0363 AC: 87 AN: 2396

European-Non Finnish (NFE) AF: 0.0328 AC: 14505 AN: 442226

Other (OTH) AF: 0.0309 AC: 1015 AN: 32854

GnomAD4 genome AF: 0.0268 AC: 4077 AN: 152300 Hom.: 78 Cov.: 32 AF XY: 0.0272 AC XY: 2024 AN XY: 74456

African (AFR) AF: 0.00676 AC: 281 AN: 41572

American (AMR) AF: 0.0174 AC: 266 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 164 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4824

European-Finnish (FIN) AF: 0.0556 AC: 589 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2517 AN: 68028

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0328 Hom.: 10

Bravo AF: 0.0223

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs70976129; hg19: chr5-74018077;