3-125232327-CTTTTTT-CTTTT

Variant names:

• chr3-125232327-CTT-C
• rs35950048
• ENST00000485866.5:c.*12_*13delAA

Variant summary

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

The ENST00000485866.5(ZNF148):​c.*12_*13delAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,255,042 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.14 (3 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.*12_*13delAA		3_prime_UTR	Exon 9 of 9	NP_068799.2	Q9UQR1-1
	ZNF148	NM_001348424.1		c.*12_*13delAA		3_prime_UTR	Exon 10 of 10	NP_001335353.1	Q9UQR1-1
	ZNF148	NM_001348425.2		c.*12_*13delAA		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.*12_*13delAA		splice_region	Exon 10 of 10	ENSP00000420448.1	Q9UQR1-1
	ZNF148	ENST00000360647.9	TSL:1 MANE Select	c.*12_*13delAA		3_prime_UTR	Exon 9 of 9	ENSP00000353863.4	Q9UQR1-1
	ZNF148	ENST00000484491.5	TSL:1	c.*12_*13delAA		3_prime_UTR	Exon 9 of 9	ENSP00000420335.1	Q9UQR1-1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 521 AN: 146306 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00499

Gnomad EAS AF: 0.000398

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00298

GnomAD2 exomes AF: 0.248 AC: 37680 AN: 152218 AF XY: 0.254

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.142 AC: 157503 AN: 1108662 Hom.: 3 AF XY: 0.147 AC XY: 80506 AN XY: 549358

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

African (AFR) AF: 0.206 AC: 4726 AN: 22988

American (AMR) AF: 0.144 AC: 4678 AN: 32460

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 3830 AN: 18368

East Asian (EAS) AF: 0.0829 AC: 2860 AN: 34480

South Asian (SAS) AF: 0.157 AC: 10282 AN: 65584

European-Finnish (FIN) AF: 0.197 AC: 6761 AN: 34380

Middle Eastern (MID) AF: 0.226 AC: 936 AN: 4144

European-Non Finnish (NFE) AF: 0.137 AC: 116424 AN: 850434

Other (OTH) AF: 0.153 AC: 7006 AN: 45824

⚠️ 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: 0.00358 AC: 524 AN: 146380 Hom.: 0 Cov.: 0 AF XY: 0.00381 AC XY: 271 AN XY: 71066

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

African (AFR) AF: 0.00148 AC: 59 AN: 39834

American (AMR) AF: 0.00367 AC: 54 AN: 14710

Ashkenazi Jewish (ASJ) AF: 0.00499 AC: 17 AN: 3410

East Asian (EAS) AF: 0.000399 AC: 2 AN: 5008

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4644

European-Finnish (FIN) AF: 0.0125 AC: 115 AN: 9170

Middle Eastern (MID) AF: 0.00360 AC: 1 AN: 278

European-Non Finnish (NFE) AF: 0.00401 AC: 266 AN: 66400

Other (OTH) AF: 0.00394 AC: 8 AN: 2032

⚠️ 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: 0.112 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; COSMIC: COSV62307859; COSMIC: COSV62307859;