1-236550992-TAAAAAAAAA-TAAAAAAAA

Variant names:

• chr1-236550992-TA-T
• rs55866014
• NM_201544.4:c.*2849delA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018072.6(HEATR1):​c.6347-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.0058 (1 hom., cov: 0)
  • Exomes 𝑓: 0.093 (1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 804 AD gene.

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.*2849delA		3_prime_UTR	Exon 10 of 10	NP_963838.1	O00214-1
	HEATR1	NM_018072.6	MANE Select	c.6347-3delT		splice_region intron	N/A	NP_060542.4
	LGALS8	NM_006499.5		c.*2849delA		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.*2849delA		3_prime_UTR	Exon 10 of 10	ENSP00000355543.4	O00214-1
	LGALS8	ENST00000450372.6	TSL:1	c.*2849delA		3_prime_UTR	Exon 12 of 12	ENSP00000408657.2	O00214-2
	HEATR1	ENST00000366582.8	TSL:5 MANE Select	c.6347-3delT		splice_region intron	N/A	ENSP00000355541.3	Q9H583

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 803 AN: 137752 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00771

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00148

Gnomad SAS AF: 0.00261

Gnomad FIN AF: 0.00808

Gnomad MID AF: 0.0278

Gnomad NFE AF: 0.00574

Gnomad OTH AF: 0.00811

GnomAD2 exomes AF: 0.194 AC: 13073 AN: 67430 AF XY: 0.200

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.0929 AC: 101516 AN: 1092986 Hom.: 1 Cov.: 18 AF XY: 0.0943 AC XY: 51235 AN XY: 543148

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

African (AFR) AF: 0.108 AC: 2742 AN: 25374

American (AMR) AF: 0.154 AC: 3523 AN: 22854

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 2360 AN: 18538

East Asian (EAS) AF: 0.156 AC: 5134 AN: 32832

South Asian (SAS) AF: 0.153 AC: 9028 AN: 59118

European-Finnish (FIN) AF: 0.0750 AC: 2279 AN: 30396

Middle Eastern (MID) AF: 0.161 AC: 609 AN: 3792

European-Non Finnish (NFE) AF: 0.0834 AC: 71145 AN: 853178

Other (OTH) AF: 0.100 AC: 4696 AN: 46904

⚠️ 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: 0.00584 AC: 804 AN: 137768 Hom.: 1 Cov.: 0 AF XY: 0.00583 AC XY: 383 AN XY: 65748

African (AFR) AF: 0.00493 AC: 186 AN: 37754

American (AMR) AF: 0.00771 AC: 106 AN: 13752

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 48 AN: 3322

East Asian (EAS) AF: 0.00148 AC: 7 AN: 4716

South Asian (SAS) AF: 0.00262 AC: 11 AN: 4192

European-Finnish (FIN) AF: 0.00808 AC: 55 AN: 6810

Middle Eastern (MID) AF: 0.0265 AC: 7 AN: 264

European-Non Finnish (NFE) AF: 0.00574 AC: 369 AN: 64234

Other (OTH) AF: 0.00806 AC: 15 AN: 1860

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
Mutation Taster		=78/22	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: rs55866014; hg19: chr1-236714292; COSMIC: COSV59381445; COSMIC: COSV59381445;