22-41382195-C-T

Variant names:

• chr22-41382195-C-T
• rs1322616609
• NM_003216.4:c.151C>T

Variant summary

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

The NM_003216.4(TEF):​c.151C>T​(p.Arg51Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,055,458 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. R51G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: TEF NM_003216.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 publications found

Genes affected

TEF (HGNC:11722): (TEF transcription factor, PAR bZIP family member) This gene encodes a member of the PAR (proline and acidic amino acid-rich) subfamily of basic region/leucine zipper (bZIP) transcription factors. It is expressed in a broad range of cells and tissues in adult animals, however, during embryonic development, TEF expression appears to be restricted to the developing anterior pituitary gland, coincident with the appearance of thyroid-stimulating hormone, beta (TSHB). Indeed, TEF can bind to, and transactivate the TSHB promoter. It shows homology (in the functional domains) with other members of the PAR-bZIP subfamily of transcription factors, which include albumin D box-binding protein (DBP), human hepatic leukemia factor (HLF) and chicken vitellogenin gene-binding protein (VBP); VBP is considered the chicken homologue of TEF. Different members of the subfamily can readily form heterodimers, and share DNA-binding, and transcriptional regulatory properties. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

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=0.2958902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEF	NM_003216.4	c.151C>T	p.Arg51Cys	missense_variant	Exon 1 of 4	ENST00000266304.9	NP_003207.1
TEF	NM_001145398.3	c.68-5156C>T		intron_variant	Intron 1 of 3		NP_001138870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEF	ENST00000266304.9	c.151C>T	p.Arg51Cys	missense_variant	Exon 1 of 4	1	NM_003216.4	ENSP00000266304.4
TEF	ENST00000406644.7	c.68-5156C>T		intron_variant	Intron 1 of 3	2		ENSP00000385256.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1055458 Hom.: 0 Cov.: 35 AF XY: 0.00000201 AC XY: 1 AN XY: 498586

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22016

American (AMR) AF: 0.00 AC: 0 AN: 8156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13002

East Asian (EAS) AF: 0.00 AC: 0 AN: 24884

South Asian (SAS) AF: 0.00 AC: 0 AN: 19570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3152

European-Non Finnish (NFE) AF: 0.00000221 AC: 2 AN: 903470

Other (OTH) AF: 0.00 AC: 0 AN: 41622

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.51	N
REVEL	Benign	0.056
Sift	Benign	0.071	T
Sift4G	Benign	0.074	T
Polyphen		0.96	D
Vest4		0.19
MutPred		0.39		Gain of catalytic residue at L52 (P = 0.0077);
MVP		0.21
MPC		1.8
ClinPred		0.93	D
GERP RS		3.3
PromoterAI		-0.065	Neutral
Varity_R		0.15
gMVP		0.22
Mutation Taster		=88/12	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: rs1322616609; hg19: chr22-41778199;