2-128268131-C-G

Variant names:

• chr2-128268131-C-G
• rs112636716
• NM_004807.3:c.*31G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004807.3(HS6ST1):​c.*31G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 1,516,644 control chromosomes in the GnomAD database, including 4,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (402 hom., cov: 33)
  • Exomes 𝑓: 0.078 (4374 hom.)
• Consequence: HS6ST1 NM_004807.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 3 publications found

Genes affected

HS6ST1 (HGNC:5201): (heparan sulfate 6-O-sulfotransferase 1) The protein encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biological activities. This enzyme is a type II integral membrane protein and is responsible for 6-O-sulfation of heparan sulfate. This enzyme does not share significant sequence similarity with other known sulfotransferases. A pseudogene located on chromosome 1 has been found for this gene. [provided by RefSeq, Jul 2008]

HS6ST1 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 15 with or without anosmia

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-128268131-C-G is Benign according to our data. Variant chr2-128268131-C-G is described in ClinVar as Benign. ClinVar VariationId is 1226324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004807.3. 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
	HS6ST1	NM_004807.3	MANE Select	c.*31G>C		3_prime_UTR	Exon 2 of 2	NP_004798.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS6ST1	ENST00000259241.7	TSL:1 MANE Select	c.*31G>C		3_prime_UTR	Exon 2 of 2	ENSP00000259241.6	O60243-1
	HS6ST1	ENST00000469019.1	TSL:4	n.361-21606G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10870 AN: 152048 Hom.: 402 Cov.: 33

Gnomad AFR AF: 0.0730

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0735

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.0605 AC: 11094 AN: 183486 AF XY: 0.0603

Gnomad AFR exome AF: 0.0674

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.0499

Gnomad EAS exome AF: 0.0262

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.0745

GnomAD4 exome AF: 0.0776 AC: 105903 AN: 1364478 Hom.: 4374 Cov.: 23 AF XY: 0.0759 AC XY: 51537 AN XY: 679008

African (AFR) AF: 0.0720 AC: 2257 AN: 31358

American (AMR) AF: 0.0571 AC: 2216 AN: 38788

Ashkenazi Jewish (ASJ) AF: 0.0514 AC: 1288 AN: 25078

East Asian (EAS) AF: 0.0265 AC: 984 AN: 37168

South Asian (SAS) AF: 0.0284 AC: 2308 AN: 81294

European-Finnish (FIN) AF: 0.0454 AC: 2171 AN: 47868

Middle Eastern (MID) AF: 0.0983 AC: 394 AN: 4008

European-Non Finnish (NFE) AF: 0.0860 AC: 89663 AN: 1042080

Other (OTH) AF: 0.0813 AC: 4622 AN: 56836

GnomAD4 genome AF: 0.0715 AC: 10875 AN: 152166 Hom.: 402 Cov.: 33 AF XY: 0.0687 AC XY: 5110 AN XY: 74410

African (AFR) AF: 0.0730 AC: 3030 AN: 41524

American (AMR) AF: 0.0734 AC: 1122 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5180

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4822

European-Finnish (FIN) AF: 0.0416 AC: 442 AN: 10626

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.0824 AC: 5598 AN: 67948

Other (OTH) AF: 0.0974 AC: 205 AN: 2104

Alfa AF: 0.0366 Hom.: 23

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.73
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs112636716; hg19: chr2-129025705;