3-125232327-CTTTTTT-CTTT

Variant names:

• chr3-125232327-CTTT-C
• rs35950048
• ENST00000485866.5:c.*11_*13delAAA

Variant summary

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

The ENST00000485866.5(ZNF148):​c.*11_*13delAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,444,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0034 (0 hom.)
• Consequence: ZNF148 ENST00000485866.5 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.598
• Publications: 1 publications found

Genes affected

ZNF148 (HGNC:12933): (zinc finger protein 148) The protein encoded by this gene is a member of the Kruppel family of zinc finger DNA binding proteins. The encoded protein activates transcription of the T-cell receptor and intestinal alkaline phosphatase genes but represses transcription of the ornithine decarboxylase, vimentin, gastrin, stomelysin, and enolase genes. Increased expression of this gene results in decreased patient survival rates from colorectal cancer, while mutations in this gene have been associated with global developmental delay, hypoplastic corpus callosum, and dysmorphic facies. [provided by RefSeq, Feb 2017]

ZNF148 Gene-Disease associations (from GenCC):

• global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000485866.5. 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
	ZNF148	NM_021964.3	MANE Select	c.*11_*13delAAA		3_prime_UTR	Exon 9 of 9	NP_068799.2	Q9UQR1-1
	ZNF148	NM_001348424.1		c.*11_*13delAAA		3_prime_UTR	Exon 10 of 10	NP_001335353.1	Q9UQR1-1
	ZNF148	NM_001348425.2		c.*11_*13delAAA		3_prime_UTR	Exon 10 of 10	NP_001335354.1	Q9UQR1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF148	ENST00000485866.5	TSL:1	c.*11_*13delAAA		splice_region	Exon 10 of 10	ENSP00000420448.1	Q9UQR1-1
	ZNF148	ENST00000360647.9	TSL:1 MANE Select	c.*11_*13delAAA		3_prime_UTR	Exon 9 of 9	ENSP00000353863.4	Q9UQR1-1
	ZNF148	ENST00000484491.5	TSL:1	c.*11_*13delAAA		3_prime_UTR	Exon 9 of 9	ENSP00000420335.1	Q9UQR1-1

Frequencies

GnomAD3 genomes AF: 0.000109 AC: 16 AN: 146482 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.0190 AC: 2890 AN: 152218 AF XY: 0.0201

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00937

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.00335 AC: 4351 AN: 1298204 Hom.: 0 AF XY: 0.00403 AC XY: 2584 AN XY: 641316

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

African (AFR) AF: 0.00439 AC: 125 AN: 28456

American (AMR) AF: 0.00910 AC: 318 AN: 34928

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 170 AN: 21674

East Asian (EAS) AF: 0.00215 AC: 81 AN: 37632

South Asian (SAS) AF: 0.00802 AC: 577 AN: 71942

European-Finnish (FIN) AF: 0.00770 AC: 302 AN: 39212

Middle Eastern (MID) AF: 0.00489 AC: 24 AN: 4912

European-Non Finnish (NFE) AF: 0.00256 AC: 2575 AN: 1005830

Other (OTH) AF: 0.00334 AC: 179 AN: 53618

⚠️ 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 AF: 0.000109 AC: 16 AN: 146558 Hom.: 0 Cov.: 0 AF XY: 0.000211 AC XY: 15 AN XY: 71182

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

African (AFR) AF: 0.0000502 AC: 2 AN: 39866

American (AMR) AF: 0.00 AC: 0 AN: 14724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4644

European-Finnish (FIN) AF: 0.000434 AC: 4 AN: 9226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66464

Other (OTH) AF: 0.000491 AC: 1 AN: 2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0158 Hom.: 1354

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.60
Mutation Taster		=100/0	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: rs35950048; hg19: chr3-124951171;