rs2016875

Variant names:

• chr8-38401517-C-A
• rs2016875
• NM_001286819.2:c.984+464C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

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]

FGFR1 Gene-Disease associations (from GenCC):

• encephalocraniocutaneous lipomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hartsfield-Bixler-Demyer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteoglophonic dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Jackson-Weiss syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC102723716 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.984+464C>A		intron_variant	Intron 6 of 10	ENST00000379957.9	NP_001273748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM2	ENST00000379957.9	c.984+464C>A		intron_variant	Intron 6 of 10	5	NM_001286819.2	ENSP00000369291.4

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

African (AFR) AF: 0.103 AC: 44 AN: 426

American (AMR) AF: 0.220 AC: 654 AN: 2966

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 39 AN: 370

East Asian (EAS) AF: 0.270 AC: 299 AN: 1106

South Asian (SAS) AF: 0.102 AC: 324 AN: 3168

European-Finnish (FIN) AF: 0.165 AC: 83 AN: 504

Middle Eastern (MID) AF: 0.167 AC: 7 AN: 42

European-Non Finnish (NFE) AF: 0.194 AC: 2202 AN: 11362

Other (OTH) AF: 0.200 AC: 190 AN: 952

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

African (AFR) AF: 0.148 AC: 6155 AN: 41508

American (AMR) AF: 0.223 AC: 3397 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1584 AN: 5166

South Asian (SAS) AF: 0.110 AC: 533 AN: 4830

European-Finnish (FIN) AF: 0.193 AC: 2043 AN: 10594

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15721 AN: 67992

Other (OTH) AF: 0.205 AC: 432 AN: 2112

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
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs2016875; hg19: chr8-38259035;