rs2016875

Positions:

• chr8-38401517-C-A
• chr8-38401517-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286819.2(LETM2):​c.984+464C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 173,038 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3402 hom., cov: 32)
  • Exomes 𝑓: 0.18 (437 hom.)
• Consequence: LETM2 NM_001286819.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290

Genes affected

LETM2 (HGNC:14648): (leucine zipper and EF-hand containing transmembrane protein 2) Predicted to enable ribosome binding activity. Predicted to be involved in cellular metal ion homeostasis. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC102723716 (HGNC:):

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.984+464C>A		intron_variant		ENST00000379957.9	NP_001273748.1
LOC102723716	XR_001745877.2	n.972+43G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LETM2	ENST00000379957.9	c.984+464C>A		intron_variant		5	NM_001286819.2	ENSP00000369291	P4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30726 AN: 152024 Hom.: 3396 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.184 AC: 3842 AN: 20896 Hom.: 437 Cov.: 0 AF XY: 0.181 AC XY: 1982 AN XY: 10952

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.202 AC: 30755 AN: 152142 Hom.: 3402 Cov.: 32 AF XY: 0.198 AC XY: 14697 AN XY: 74368

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.205

Alfa AF: 0.141 Hom.: 412

Bravo AF: 0.209

Asia WGS AF: 0.197 AC: 684 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.7
DANN	Benign	0.67

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: rs2016875; hg19: chr8-38259035;