6-105078610-G-C

Variant names:

• chr6-105078610-G-C
• NM_001004317.4:c.580G>C

Variant summary

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

The NM_001004317.4(LIN28B):​c.580G>C​(p.Glu194Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 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: LIN28B NM_001004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

Genes affected

LIN28B (HGNC:32207): (lin-28 homolog B) The protein encoded by this gene belongs to the lin-28 family, which is characterized by the presence of a cold-shock domain and a pair of CCHC zinc finger domains. This gene is highly expressed in testis, fetal liver, placenta, and in primary human tumors and cancer cell lines. It is negatively regulated by microRNAs that target sites in the 3' UTR, and overexpression of this gene in primary tumors is linked to the repression of let-7 family of microRNAs and derepression of let-7 targets, which facilitates cellular transformation. [provided by RefSeq, Jun 2012]

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=0.2476218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIN28B	NM_001004317.4	c.580G>C	p.Glu194Gln	missense_variant	Exon 4 of 4	ENST00000345080.5	NP_001004317.1
LIN28B	NM_001410939.1	c.604G>C	p.Glu202Gln	missense_variant	Exon 5 of 5		NP_001397868.1
LIN28B	XM_006715477.3	c.637G>C	p.Glu213Gln	missense_variant	Exon 5 of 5		XP_006715540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIN28B	ENST00000345080.5	c.580G>C	p.Glu194Gln	missense_variant	Exon 4 of 4	1	NM_001004317.4	ENSP00000344401.4
LIN28B	ENST00000637759.1	c.604G>C	p.Glu202Gln	missense_variant	Exon 5 of 5	5		ENSP00000490468.1
LIN28B	ENST00000635857.1	c.*8G>C		downstream_gene_variant		5		ENSP00000489735.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

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

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.580G>C (p.E194Q) alteration is located in exon 4 (coding exon 4) of the LIN28B gene. This alteration results from a G to C substitution at nucleotide position 580, causing the glutamic acid (E) at amino acid position 194 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.91	.;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	.;D
Sift4G	Benign	0.070	.;T
Polyphen		0.99	.;D
Vest4		0.32
MutPred		0.12		.;Loss of stability (P = 0.1837);
MVP		0.51
MPC		1.3
ClinPred		0.90	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-105526485;