14-24192192-G-T

Position:

• chr14-24192192-G-T

Variant summary

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

The NM_006405.7(TM9SF1):​c.1132C>A​(p.Leu378Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM9SF1 NM_006405.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.77

Genes affected

TM9SF1 (HGNC:11864): (transmembrane 9 superfamily member 1) Predicted to be involved in protein localization to membrane. Predicted to be located in autophagosome membrane; cytoplasmic vesicle; and lysosomal membrane. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM9SF1	NM_006405.7	c.1132C>A	p.Leu378Ile	missense_variant	4/6	ENST00000261789.9	NP_006396.2
TM9SF1	NM_001289006.2	c.871C>A	p.Leu291Ile	missense_variant	4/6		NP_001275935.1
TM9SF1	NM_001014842.3	c.1132C>A	p.Leu378Ile	missense_variant	4/5		NP_001014842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM9SF1	ENST00000261789.9	c.1132C>A	p.Leu378Ile	missense_variant	4/6	1	NM_006405.7	ENSP00000261789	P1
	ENST00000655961.1	n.764-459G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

May 08, 2024

The c.1132C>A (p.L378I) alteration is located in exon 4 (coding exon 3) of the TM9SF1 gene. This alteration results from a C to A substitution at nucleotide position 1132, causing the leucine (L) at amino acid position 378 to be replaced by an isoleucine (I). 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	0.29
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.97	D;.;.;.;.
Vest4		0.57
MutPred		0.75		Gain of glycosylation at T379 (P = 0.1026);Gain of glycosylation at T379 (P = 0.1026);.;Gain of glycosylation at T379 (P = 0.1026);.;
MVP		0.81
MPC		1.3
ClinPred		0.93	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.49

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: chr14-24661398;