15-83136496-A-G

Position:

• chr15-83136496-A-G

Variant summary

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

The NM_023003.5(TM6SF1):​c.937A>G​(p.Ile313Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I313T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM6SF1 NM_023003.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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

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=0.23308426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM6SF1	NM_023003.5	c.937A>G	p.Ile313Val	missense_variant	10/10	ENST00000322019.14
HDGFL3	NM_016073.4	c.*2774T>C		3_prime_UTR_variant	6/6	ENST00000299633.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM6SF1	ENST00000322019.14	c.937A>G	p.Ile313Val	missense_variant	10/10	1	NM_023003.5	P1
HDGFL3	ENST00000299633.7	c.*2774T>C		3_prime_UTR_variant	6/6	1	NM_016073.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Mar 08, 2024

The c.937A>G (p.I313V) alteration is located in exon 10 (coding exon 10) of the TM6SF1 gene. This alteration results from a A to G substitution at nucleotide position 937, causing the isoleucine (I) at amino acid position 313 to be replaced by a valine (V). 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	0.074
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.044
Sift	Benign	0.030	D;D
Sift4G	Benign	0.075	T;T
Polyphen		0.0060	B;.
Vest4		0.35
MutPred		0.24		Gain of disorder (P = 0.1564);.;
MVP		0.048
MPC		0.23
ClinPred		0.70	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-83805248;