NM_006701.5:c.37C>A

Variant names:

• chr18-79988356-G-T
• rs727502794
• NM_006701.5:c.37C>A

Variant summary

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

The NM_006701.5(TXNL4A):​c.37C>A​(p.Gln13Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,514 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TXNL4A NM_006701.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.67
• Publications: 0 publications found

Genes affected

TXNL4A (HGNC:30551): (thioredoxin like 4A) The protein encoded by this gene is a member of the U5 small ribonucleoprotein particle (snRNP), and is involved in pre-mRNA splicing. This protein contains a thioredoxin-like fold and it is expected to interact with multiple proteins. Protein-protein interactions have been observed with the polyglutamine tract-binding protein 1 (PQBP1). Mutations in both the coding region and promoter region of this gene have been associated with Burn-McKeown syndrome, which is a rare disorder characterized by craniofacial dysmorphisms, cardiac defects, hearing loss, and bilateral choanal atresia. A pseudogene of this gene is found on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

TXNL4A Gene-Disease associations (from GenCC):

• choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

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=0.3726195).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006701.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNL4A	NM_006701.5	MANE Select	c.37C>A	p.Gln13Lys	missense	Exon 1 of 3	NP_006692.1
	TXNL4A	NM_001305557.2		c.37C>A	p.Gln13Lys	missense	Exon 1 of 3	NP_001292486.1
	TXNL4A	NR_131175.2		n.208C>A		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNL4A	ENST00000269601.10	TSL:1 MANE Select	c.37C>A	p.Gln13Lys	missense	Exon 1 of 3	ENSP00000269601.4
	TXNL4A	ENST00000355491.5	TSL:1	n.37C>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000347678.4
	TXNL4A	ENST00000585474.5	TSL:1	c.-60-10655C>A		intron	N/A	ENSP00000465572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406514 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695542

⚠️ 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: 31738

American (AMR) AF: 0.00 AC: 0 AN: 38104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.00 AC: 0 AN: 36376

South Asian (SAS) AF: 0.00 AC: 0 AN: 80166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082044

Other (OTH) AF: 0.00 AC: 0 AN: 57976

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.25	T
Sift4G	Benign	0.74	T
Polyphen		0.14	B
Vest4		0.54
MutPred		0.52		Gain of methylation at Q13 (P = 0.0137)
MVP		0.37
MPC		2.2
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.89
gMVP		0.96
Mutation Taster		=12/88	disease causing

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: rs727502794; hg19: chr18-77748356;