chr20-32145169-A-G

Variant names:

• chr20-32145169-A-G
• rs376848441
• NM_014742.4:c.731A>G

Variant summary

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

The NM_014742.4(TM9SF4):​c.731A>G​(p.Lys244Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K244M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TM9SF4 NM_014742.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54
• Publications: 0 publications found

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]

TM9SF4 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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=0.18748114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF4	NM_014742.4	c.731A>G	p.Lys244Arg	missense_variant	Exon 7 of 18	ENST00000398022.7	NP_055557.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM9SF4	ENST00000398022.7	c.731A>G	p.Lys244Arg	missense_variant	Exon 7 of 18	1	NM_014742.4	ENSP00000381104.2
TM9SF4	ENST00000217315.9	c.680A>G	p.Lys227Arg	missense_variant	Exon 7 of 18	2		ENSP00000217315.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		4.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.095
Sift	Benign	0.13	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.012	B;.
Vest4		0.25
MutPred		0.39		Loss of methylation at K244 (P = 8e-04);.;
MVP		0.23
MPC		0.64
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.097
gMVP		0.32
Mutation Taster		=83/17	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: rs376848441; hg19: chr20-30732972;