1-236550992-TAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr1-236550992-T-TAAAA
• rs55866014
• NM_201544.4:c.*2846_*2849dupAAAA

Variant summary

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

The NM_018072.6(HEATR1):​c.6347-6_6347-3dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00075 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 14 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.*2846_*2849dupAAAA		3_prime_UTR	Exon 10 of 10	NP_963838.1	O00214-1
	HEATR1	NM_018072.6	MANE Select	c.6347-6_6347-3dupTTTT		splice_region intron	N/A	NP_060542.4
	LGALS8	NM_006499.5		c.*2846_*2849dupAAAA		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.*2846_*2849dupAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000355543.4	O00214-1
	LGALS8	ENST00000450372.6	TSL:1	c.*2846_*2849dupAAAA		3_prime_UTR	Exon 12 of 12	ENSP00000408657.2	O00214-2
	HEATR1	ENST00000366582.8	TSL:5 MANE Select	c.6347-6_6347-3dupTTTT		splice_region intron	N/A	ENSP00000355541.3	Q9H583

Frequencies

GnomAD3 genomes AF: 0.000102 AC: 14 AN: 137786 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000238

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000754 AC: 842 AN: 1116538 Hom.: 0 Cov.: 18 AF XY: 0.000722 AC XY: 401 AN XY: 555592

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

African (AFR) AF: 0.000307 AC: 8 AN: 26078

American (AMR) AF: 0.000548 AC: 13 AN: 23740

Ashkenazi Jewish (ASJ) AF: 0.000736 AC: 14 AN: 19022

East Asian (EAS) AF: 0.000322 AC: 11 AN: 34212

South Asian (SAS) AF: 0.000377 AC: 23 AN: 61084

European-Finnish (FIN) AF: 0.000320 AC: 10 AN: 31226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3892

European-Non Finnish (NFE) AF: 0.000836 AC: 727 AN: 869262

Other (OTH) AF: 0.000750 AC: 36 AN: 48022

⚠️ 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: 0.000102 AC: 14 AN: 137806 Hom.: 0 Cov.: 0 AF XY: 0.000137 AC XY: 9 AN XY: 65774

African (AFR) AF: 0.0000530 AC: 2 AN: 37760

American (AMR) AF: 0.00 AC: 0 AN: 13760

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4716

South Asian (SAS) AF: 0.000239 AC: 1 AN: 4192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.000171 AC: 11 AN: 64244

Other (OTH) AF: 0.00 AC: 0 AN: 1862

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		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55866014;

hg19: chr1-236714292;