22-37065581-G-A

Variant names:

• chr22-37065581-G-A
• rs560949530
• NM_001374504.1:c.*499C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001374504.1(TMPRSS6):​c.*499C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 163,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.164

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/152332) while in subpopulation NFE AF = 0.0019 (129/68038). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.*499C>T		3_prime_UTR_variant	Exon 18 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.*499C>T		3_prime_UTR_variant	Exon 18 of 18		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000636 AC: 7 AN: 11002 Hom.: 0 Cov.: 0 AF XY: 0.000865 AC XY: 5 AN XY: 5782

African (AFR) AF: 0.00 AC: 0 AN: 320

American (AMR) AF: 0.000533 AC: 1 AN: 1876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 144

East Asian (EAS) AF: 0.00 AC: 0 AN: 598

South Asian (SAS) AF: 0.000856 AC: 1 AN: 1168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.000826 AC: 5 AN: 6056

Other (OTH) AF: 0.00 AC: 0 AN: 544

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000899 AC XY: 67 AN XY: 74490

African (AFR) AF: 0.000361 AC: 15 AN: 41564

American (AMR) AF: 0.000718 AC: 11 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00116

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcytic anemia Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		-0.16
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs560949530; hg19: chr22-37461621;