1-26426415-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024674.6(LIN28A):c.587A>G(p.Glu196Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIN28A NM_024674.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

Genes affected

LIN28A (HGNC:15986): (lin-28 homolog A) This gene encodes a LIN-28 family RNA-binding protein that acts as a posttranscriptional regulator of genes involved in developmental timing and self-renewal in embryonic stem cells. The encoded protein functions through direct interaction with target mRNAs and by disrupting the maturation of certain miRNAs involved in embryonic development. This protein prevents the terminal processing of the LET7 family of microRNAs which are major regulators of cellular growth and differentiation. Aberrant expression of this gene is associated with cancer progression in multiple tissues. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23049584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIN28A	NM_024674.6	c.587A>G	p.Glu196Gly	missense_variant	4/4	ENST00000326279.11
LIN28A	XM_011542148.3	c.587A>G	p.Glu196Gly	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIN28A	ENST00000326279.11	c.587A>G	p.Glu196Gly	missense_variant	4/4	1	NM_024674.6	P1
LIN28A	ENST00000254231.4	c.587A>G	p.Glu196Gly	missense_variant	4/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135894

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.587A>G (p.E196G) alteration is located in exon 4 (coding exon 4) of the LIN28A gene. This alteration results from a A to G substitution at nucleotide position 587, causing the glutamic acid (E) at amino acid position 196 to be replaced by a glycine (G). 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	0.091
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.71	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.095	T;T
Polyphen		1.0	D;D
Vest4		0.18
MutPred		0.15		Loss of stability (P = 0.0506);Loss of stability (P = 0.0506);
MVP		0.78
MPC		0.61
ClinPred		0.67	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.45

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: rs1283208848; hg19: chr1-26752906;