6-31162466-ACTTC-ACTTCCTTC

Variant names:

• chr6-31162466-A-ACTTC
• rs3216869
• NM_007109.3:c.798-6_798-3dupCTTC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_007109.3(TCF19):​c.798-6_798-3dupCTTC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TCF19 NM_007109.3 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

TCF19 (HGNC:11629): (transcription factor 19) This gene encodes a protein that contains a PHD-type zinc finger domain and likely functions as a transcription factor. The encoded protein plays a role proliferation and apoptosis of pancreatic beta cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.6753372 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.9, offset of 0 (no position change), new splice context is: gtgtcacttccttccttcAGaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007109.3. 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
	TCF19	NM_007109.3	MANE Select	c.798-6_798-3dupCTTC		splice_acceptor intron	N/A	NP_009040.2	A0A1U9X8M7
	TCF19	NM_001077511.2		c.798-6_798-3dupCTTC		splice_acceptor intron	N/A	NP_001070979.1	A0A1U9X8M7
	TCF19	NM_001318908.2		c.798-6_798-3dupCTTC		splice_acceptor intron	N/A	NP_001305837.1	Q9Y242

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF19	ENST00000376257.8	TSL:1 MANE Select	c.798-11_798-10insCTTC		intron	N/A	ENSP00000365433.3	Q9Y242
	TCF19	ENST00000376255.4	TSL:1	c.798-11_798-10insCTTC		intron	N/A	ENSP00000365431.4	Q9Y242
	TCF19	ENST00000706778.1		c.798-11_798-10insCTTC		intron	N/A	ENSP00000516543.1	Q9Y242

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3216869; hg19: chr6-31130243;