22-37065577-G-C

Variant names:

• chr22-37065577-G-C
• rs117575523
• NM_001374504.1:c.*503C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001374504.1(TMPRSS6):​c.*503C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 163,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.259
• Publications: 0 publications found

Genes affected

TMPRSS6 (HGNC:16517): (transmembrane serine protease 6) The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS6 Gene-Disease associations (from GenCC):

• IRIDA syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-37065577-G-C is Benign according to our data. Variant chr22-37065577-G-C is described in ClinVar as Benign. ClinVar VariationId is 341571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000946 (144/152292) while in subpopulation EAS AF = 0.0178 (92/5172). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. 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
	TMPRSS6	NM_001374504.1	MANE Select	c.*503C>G		3_prime_UTR	Exon 18 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.*503C>G		3_prime_UTR	Exon 19 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.*503C>G		3_prime_UTR	Exon 18 of 18	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.*503C>G		3_prime_UTR	Exon 18 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.*503C>G		3_prime_UTR	Exon 19 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.*503C>G		3_prime_UTR	Exon 18 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152180 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00177 AC: 19 AN: 10760 Hom.: 0 Cov.: 0 AF XY: 0.00176 AC XY: 10 AN XY: 5690

African (AFR) AF: 0.00 AC: 0 AN: 328

American (AMR) AF: 0.00163 AC: 3 AN: 1838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 138

East Asian (EAS) AF: 0.0241 AC: 14 AN: 582

South Asian (SAS) AF: 0.000890 AC: 1 AN: 1124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.000169 AC: 1 AN: 5910

Other (OTH) AF: 0.00 AC: 0 AN: 540

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152292 Hom.: 6 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74462

African (AFR) AF: 0.000193 AC: 8 AN: 41552

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000793

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.69
PhyloP100		0.26

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: rs117575523; hg19: chr22-37461617;