rs79040751

Variant names:

• chr5-38493734-G-T
• rs79040751
• NM_001127671.2:c.1937C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-38493734-G-T
• chr5-38493734-G-A
• chr5-38493734-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127671.2(LIFR):​c.1937C>A​(p.Thr646Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,082 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (15 hom.)
• Consequence: LIFR NM_001127671.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 1.43
• Publications: 8 publications found

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]

LIFR Gene-Disease associations (from GenCC):

• Stüve-Wiedemann syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Stüve-Wiedemann syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0153023).
• BP6: Variant 5-38493734-G-T is Benign according to our data. Variant chr5-38493734-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235543.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 = 0.00808 (1230/152250) while in subpopulation AFR AF = 0.0271 (1128/41556). AF 95% confidence interval is 0.0258. There are 5 homozygotes in GnomAd4. There are 609 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127671.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIFR	NM_001127671.2	MANE Select	c.1937C>A	p.Thr646Asn	missense	Exon 14 of 20	NP_001121143.1	P42702-1
	LIFR	NM_001364297.2		c.1937C>A	p.Thr646Asn	missense	Exon 14 of 20	NP_001351226.1	P42702-1
	LIFR	NM_002310.6		c.1937C>A	p.Thr646Asn	missense	Exon 14 of 20	NP_002301.1	P42702-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIFR	ENST00000453190.7	TSL:2 MANE Select	c.1937C>A	p.Thr646Asn	missense	Exon 14 of 20	ENSP00000398368.2	P42702-1
	LIFR	ENST00000263409.8	TSL:1	c.1937C>A	p.Thr646Asn	missense	Exon 14 of 20	ENSP00000263409.4	P42702-1
	LIFR	ENST00000503088.1	TSL:1	n.2100C>A		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152132 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00206 AC: 518 AN: 251466 AF XY: 0.00153

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000984 AC: 1439 AN: 1461832 Hom.: 15 Cov.: 31 AF XY: 0.000798 AC XY: 580 AN XY: 727224

African (AFR) AF: 0.0279 AC: 933 AN: 33478

American (AMR) AF: 0.00212 AC: 95 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000207 AC: 230 AN: 1111960

Other (OTH) AF: 0.00267 AC: 161 AN: 60392

GnomAD4 genome AF: 0.00808 AC: 1230 AN: 152250 Hom.: 5 Cov.: 32 AF XY: 0.00818 AC XY: 609 AN XY: 74436

African (AFR) AF: 0.0271 AC: 1128 AN: 41556

American (AMR) AF: 0.00425 AC: 65 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00664 Hom.: 12

Bravo AF: 0.00962

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0247 AC: 109

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00231 AC: 281

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Stuve-Wiedemann syndrome (2)
-	1	-	Congenital anomaly of kidney and urinary tract (1)
-	-	1	Connective tissue disorder (1)
-	-	1	LIFR-related disorder (1)
-	-	1	Stüve-Wiedemann syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.076
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.059	T
Polyphen		0.22	B
Vest4		0.44
MVP		0.55
MPC		0.12
ClinPred		0.022	T
GERP RS		-1.1
Varity_R		0.18
gMVP		0.60
Mutation Taster		=86/14	disease causing (ClinVar)

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: rs79040751; hg19: chr5-38493836; COSMIC: COSV99665894;