15-83112825-C-G

Variant names:

• chr15-83112825-C-G
• rs368481259
• NM_023003.5:c.121C>G

Variant summary

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

The NM_023003.5(TM6SF1):​c.121C>G​(p.Leu41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TM6SF1 NM_023003.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.674
• Publications: 0 publications found

Genes affected

TM6SF1 (HGNC:11860): (transmembrane 6 superfamily member 1) Predicted to be integral component of membrane. Predicted to be active in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

HDGFL3 (HGNC:24937): (HDGF like 3) Predicted to enable double-stranded DNA binding activity; microtubule binding activity; and transcription coregulator activity. Predicted to be involved in several processes, including microtubule polymerization; negative regulation of microtubule depolymerization; and neuron projection development. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.08577871).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023003.5. 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
	TM6SF1	NM_023003.5	MANE Select	c.121C>G	p.Leu41Val	missense	Exon 2 of 10	NP_075379.2	Q9BZW5-1
	TM6SF1	NM_001353878.2		c.121C>G	p.Leu41Val	missense	Exon 2 of 11	NP_001340807.1
	TM6SF1	NM_001144903.3		c.121C>G	p.Leu41Val	missense	Exon 2 of 9	NP_001138375.1	Q9BZW5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM6SF1	ENST00000322019.14	TSL:1 MANE Select	c.121C>G	p.Leu41Val	missense	Exon 2 of 10	ENSP00000317000.9	Q9BZW5-1
	TM6SF1	ENST00000565774.5	TSL:1	c.121C>G	p.Leu41Val	missense	Exon 2 of 9	ENSP00000457477.1	Q9BZW5-2
	TM6SF1	ENST00000379390.10	TSL:1	c.121C>G	p.Leu41Val	missense	Exon 2 of 7	ENSP00000368700.6	Q6P4D7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251468 AF XY: 0.0000147

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: 1461838 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.67
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.015
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.049	B
Vest4		0.14
MVP		0.18
MPC		0.21
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.081
gMVP		0.54
Mutation Taster		=89/10	polymorphism

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: rs368481259; hg19: chr15-83781577;