chr19-35739594-G-A

Variant names:

• chr19-35739594-G-A
• rs774295280
• NM_024660.4:c.754C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024660.4(IGFLR1):​c.754C>T​(p.Arg252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IGFLR1 NM_024660.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 2 publications found

Genes affected

IGFLR1 (HGNC:23620): (IGF like family receptor 1) Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267120 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13577354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFLR1	NM_024660.4	c.754C>T	p.Arg252Cys	missense_variant	Exon 5 of 5	ENST00000246532.6	NP_078936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFLR1	ENST00000246532.6	c.754C>T	p.Arg252Cys	missense_variant	Exon 5 of 5	1	NM_024660.4	ENSP00000246532.1
ENSG00000267120	ENST00000589807.1	n.*1248C>T		non_coding_transcript_exon_variant	Exon 11 of 11	2		ENSP00000472696.1
ENSG00000267120	ENST00000589807.1	n.*1248C>T		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000472696.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250710 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726886

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.754C>T (p.R252C) alteration is located in exon 5 (coding exon 4) of the IGFLR1 gene. This alteration results from a C to T substitution at nucleotide position 754, causing the arginine (R) at amino acid position 252 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;M
PhyloP100		1.2
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.0	D;.;.;.
REVEL	Benign	0.032
Sift	Uncertain	0.027	D;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.25	B;B;.;B
Vest4		0.26
MVP		0.34
MPC		0.54
ClinPred		0.74	D
GERP RS		2.8
Varity_R		0.13
gMVP		0.46
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774295280; hg19: chr19-36230495; COSMIC: COSV53073532; COSMIC: COSV53073532;