rs12304921

Variant names:

• chr12-50963759-A-G
• rs12304921
• NM_001109619.4:c.229+2657A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001109619.4(HIGD1C):​c.229+2657A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,184 control chromosomes in the GnomAD database, including 2,918 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2918 hom., cov: 32)
• Consequence: HIGD1C NM_001109619.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910
• Publications: 34 publications found

Genes affected

HIGD1C (HGNC:28044): (HIG1 hypoxia inducible domain family member 1C) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289695 (HGNC:):

SLC11A2 (HGNC:10908): (solute carrier family 11 member 2) This gene encodes a member of the solute carrier family 11 protein family. The product of this gene transports divalent metals and is involved in iron absorption. Mutations in this gene are associated with hypochromic microcytic anemia with iron overload. A related solute carrier family 11 protein gene is located on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]

SLC11A2 Gene-Disease associations (from GenCC):

• microcytic anemia with liver iron overload

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIGD1C	NM_001109619.4	c.229+2657A>G		intron_variant	Intron 4 of 4	ENST00000695931.1	NP_001103089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIGD1C	ENST00000695931.1	c.229+2657A>G		intron_variant	Intron 4 of 4		NM_001109619.4	ENSP00000512274.1
HIGD1C	ENST00000398455.3	c.229+2657A>G		intron_variant	Intron 2 of 2	1		ENSP00000381473.3
ENSG00000289695	ENST00000695929.1	n.*534+2657A>G		intron_variant	Intron 6 of 6			ENSP00000512272.1
HIGD1C	ENST00000695930.1	c.253+2657A>G		intron_variant	Intron 3 of 3			ENSP00000512273.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27806 AN: 152066 Hom.: 2910 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.183 AC: 27846 AN: 152184 Hom.: 2918 Cov.: 32 AF XY: 0.189 AC XY: 14034 AN XY: 74406

African (AFR) AF: 0.173 AC: 7202 AN: 41516

American (AMR) AF: 0.165 AC: 2523 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 704 AN: 3468

East Asian (EAS) AF: 0.499 AC: 2575 AN: 5164

South Asian (SAS) AF: 0.288 AC: 1388 AN: 4824

European-Finnish (FIN) AF: 0.188 AC: 1991 AN: 10596

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10717 AN: 68002

Other (OTH) AF: 0.174 AC: 368 AN: 2112

Alfa AF: 0.173 Hom.: 5999

Bravo AF: 0.180

Asia WGS AF: 0.362 AC: 1264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.91
PhyloP100		0.091
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: rs12304921; hg19: chr12-51357542;