rs3729743

Positions:

• chr5-38493803-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127671.2(LIFR):​c.1886-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,604,856 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (39 hom.)
• Consequence: LIFR NM_001127671.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.145

Genes affected

LIFR (HGNC:6597): (LIF receptor subunit alpha) This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-38493803-G-A is Benign according to our data. Variant chr5-38493803-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2143/152128) while in subpopulation AFR AF= 0.0479 (1986/41454). AF 95% confidence interval is 0.0462. There are 43 homozygotes in gnomad4. There are 1027 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIFR	NM_001127671.2	c.1886-18C>T		intron_variant		ENST00000453190.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIFR	ENST00000453190.7	c.1886-18C>T		intron_variant		2	NM_001127671.2	P1
LIFR	ENST00000263409.8	c.1886-18C>T		intron_variant		1		P1
LIFR	ENST00000503088.1	n.2049-18C>T		intron_variant, non_coding_transcript_variant		1
LIFR	ENST00000506003.5	c.*64-18C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2131 AN: 152010 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00362 AC: 910 AN: 251306 Hom.: 21 AF XY: 0.00257 AC XY: 349 AN XY: 135820

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00160 AC: 2320 AN: 1452728 Hom.: 39 Cov.: 28 AF XY: 0.00130 AC XY: 944 AN XY: 723394

Gnomad4 AFR exome AF: 0.0491

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.0141 AC: 2143 AN: 152128 Hom.: 43 Cov.: 32 AF XY: 0.0138 AC XY: 1027 AN XY: 74382

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00878 Hom.: 8

Bravo AF: 0.0164

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Stüve-Wiedemann syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.55

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: rs3729743; hg19: chr5-38493905;