20-32161361-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014742.4(TM9SF4):c.1775A>C(p.Asn592Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM9SF4 NM_014742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

Genes affected

TM9SF4 (HGNC:30797): (transmembrane 9 superfamily member 4) Involved in several processes, including positive regulation of protein localization; regulation of intracellular pH; and vacuolar proton-transporting V-type ATPase complex assembly. Located in Golgi apparatus and early endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TM9SF4
• BP4: Computational evidence support a benign effect (MetaRNN=0.33991712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM9SF4	NM_014742.4	c.1775A>C	p.Asn592Thr	missense_variant	17/18	ENST00000398022.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM9SF4	ENST00000398022.7	c.1775A>C	p.Asn592Thr	missense_variant	17/18	1	NM_014742.4	P1
TM9SF4	ENST00000217315.9	c.1724A>C	p.Asn575Thr	missense_variant	17/18	2
TM9SF4	ENST00000479591.1	n.269A>C		non_coding_transcript_exon_variant	1/2	2
TM9SF4	ENST00000495749.1	n.1055A>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Apr 14, 2022

The c.1775A>C (p.N592T) alteration is located in exon 17 (coding exon 17) of the TM9SF4 gene. This alteration results from a A to C substitution at nucleotide position 1775, causing the asparagine (N) at amino acid position 592 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Benign	0.81
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.029
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	2.7	N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0080	B;.
Vest4		0.72
MutPred		0.52		Loss of stability (P = 0.0436);.;
MVP		0.13
MPC		0.75
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.65

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: chr20-30749164;