chr6-105078414-A-T

Variant names:

• chr6-105078414-A-T
• rs1381916811
• NM_001004317.4:c.384A>T

Variant summary

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

The NM_001004317.4(LIN28B):​c.384A>T​(p.Arg128Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R128R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIN28B NM_001004317.4 missense, splice_region
• Scores: Splicing: ADA: 0.09124
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004317.4. 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
	LIN28B	NM_001004317.4	MANE Select	c.384A>T	p.Arg128Ser	missense splice_region	Exon 4 of 4	NP_001004317.1	Q6ZN17-1
	LIN28B	NM_001410939.1		c.408A>T	p.Arg136Ser	missense splice_region	Exon 5 of 5	NP_001397868.1	A0A1B0GVD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIN28B	ENST00000345080.5	TSL:1 MANE Select	c.384A>T	p.Arg128Ser	missense splice_region	Exon 4 of 4	ENSP00000344401.4	Q6ZN17-1
	LIN28B	ENST00000637759.1	TSL:5	c.408A>T	p.Arg136Ser	missense splice_region	Exon 5 of 5	ENSP00000490468.1	A0A1B0GVD3
	LIN28B	ENST00000635857.1	TSL:5	c.441A>T	p.Arg147Ser	missense splice_region	Exon 6 of 6	ENSP00000489735.1	A0A1B0GTK2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244802 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1435270 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708856

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32696

American (AMR) AF: 0.0000234 AC: 1 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.00 AC: 0 AN: 84506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093134

Other (OTH) AF: 0.00 AC: 0 AN: 59060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000366374), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.027	D
Sift4G	Benign	0.10	T
Polyphen		0.18	B
Vest4		0.65
MutPred		0.44		Loss of MoRF binding (P = 0.0322)
MVP		0.74
MPC		1.6
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.80
gMVP		0.68
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.091
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.050		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: rs1381916811; hg19: chr6-105526289;