chr1-236550992-T-TAAAAAAA

Variant names:

• chr1-236550992-T-TAAAAAAA
• rs55866014
• NM_201544.4:c.*2843_*2849dupAAAAAAA

Variant summary

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

The NM_018072.6(HEATR1):​c.6347-9_6347-3dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: HEATR1 NM_018072.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.486
• Publications: 1 publications found

Genes affected

LGALS8 (HGNC:6569): (galectin 8) This gene encodes a member of the galectin family. Galectins are beta-galactoside-binding animal lectins with conserved carbohydrate recognition domains. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, and RNA splicing. This gene is widely expressed in tumoral tissues and seems to be involved in integrin-like cell interactions. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

HEATR1 (HGNC:25517): (HEAT repeat containing 1) Enables RNA binding activity. Involved in positive regulation of rRNA processing and positive regulation of transcription by RNA polymerase I. Located in fibrillar center and mitochondrion. Implicated in pancreatic ductal carcinoma. Biomarker of glioblastoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018072.6. 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
	LGALS8	NM_201544.4	MANE Select	c.*2843_*2849dupAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_963838.1	O00214-1
	HEATR1	NM_018072.6	MANE Select	c.6347-9_6347-3dupTTTTTTT		splice_region intron	N/A	NP_060542.4
	LGALS8	NM_006499.5		c.*2843_*2849dupAAAAAAA		3_prime_UTR	Exon 12 of 12	NP_006490.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LGALS8	ENST00000366584.9	TSL:1 MANE Select	c.*2843_*2849dupAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000355543.4	O00214-1
	LGALS8	ENST00000450372.6	TSL:1	c.*2843_*2849dupAAAAAAA		3_prime_UTR	Exon 12 of 12	ENSP00000408657.2	O00214-2
	HEATR1	ENST00000366582.8	TSL:5 MANE Select	c.6347-9_6347-3dupTTTTTTT		splice_region intron	N/A	ENSP00000355541.3	Q9H583

Frequencies

GnomAD3 genomes AF: 0.0000218 AC: 3 AN: 137784 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.000147

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000311

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000716 AC: 8 AN: 1117896 Hom.: 0 Cov.: 18 AF XY: 0.00000180 AC XY: 1 AN XY: 556228

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

African (AFR) AF: 0.0000383 AC: 1 AN: 26094

American (AMR) AF: 0.00 AC: 0 AN: 23786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19030

East Asian (EAS) AF: 0.00 AC: 0 AN: 34238

South Asian (SAS) AF: 0.0000163 AC: 1 AN: 61164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 0.00000689 AC: 6 AN: 870366

Other (OTH) AF: 0.00 AC: 0 AN: 48068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000400915), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000218 AC: 3 AN: 137784 Hom.: 0 Cov.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65728

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

African (AFR) AF: 0.00 AC: 0 AN: 37692

American (AMR) AF: 0.00 AC: 0 AN: 13748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4736

South Asian (SAS) AF: 0.00 AC: 0 AN: 4208

European-Finnish (FIN) AF: 0.000147 AC: 1 AN: 6820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000311 AC: 2 AN: 64254

Other (OTH) AF: 0.00 AC: 0 AN: 1852

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00462622), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.49

Splicing

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

Other links and lift over

dbSNP: rs55866014; hg19: chr1-236714292;