18-75285570-G-C

Variant names:

• chr18-75285570-G-C
• rs375819140
• NM_001308210.2:c.163G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308210.2(TSHZ1):​c.163G>C​(p.Glu55Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E55K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSHZ1 NM_001308210.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

TSHZ1 (HGNC:10669): (teashirt zinc finger homeobox 1) This gene encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. The encoded protein is a member of the teashirt C2H2-type zinc-finger protein family and may be involved in transcriptional regulation of developmental processes. Mutations in this gene may be associated with congenital aural atresia syndrome. [provided by RefSeq, Jan 2012]

TSHZ1 Gene-Disease associations (from GenCC):

• aural atresia, congenital

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• congenital vertical talus

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27116102).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308210.2. 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
	TSHZ1	NM_001308210.2	MANE Select	c.163G>C	p.Glu55Gln	missense	Exon 2 of 2	NP_001295139.1	Q6ZSZ6-1
	TSHZ1	NM_005786.6		c.28G>C	p.Glu10Gln	missense	Exon 2 of 2	NP_005777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHZ1	ENST00000580243.3	TSL:2 MANE Select	c.163G>C	p.Glu55Gln	missense	Exon 2 of 2	ENSP00000464391.1	Q6ZSZ6-1
	TSHZ1	ENST00000322038.5	TSL:1	c.28G>C	p.Glu10Gln	missense	Exon 2 of 2	ENSP00000323584.5	Q6ZSZ6-2
	TSHZ1	ENST00000560918.2	TSL:4	c.28G>C	p.Glu10Gln	missense	Exon 2 of 2	ENSP00000453834.2	H0YN23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443126 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714322

African (AFR) AF: 0.00 AC: 0 AN: 33034

American (AMR) AF: 0.00 AC: 0 AN: 43842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.00 AC: 0 AN: 85246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098396

Other (OTH) AF: 0.00 AC: 0 AN: 59408

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.26
Sift	Benign	0.43	T
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.087		Loss of helix (P = 0.0558)
MVP		0.59
MPC		0.98
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.14
Mutation Taster		=86/14	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: rs375819140; hg19: chr18-72997525;