NM_001374504.1:c.*251T>G

Variant names:

• chr22-37065829-A-C
• rs1926220781
• NM_001374504.1:c.*251T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001374504.1(TMPRSS6):​c.*251T>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 0.00000992 in 403,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*251T>G		3_prime_UTR	Exon 18 of 18	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.*251T>G		3_prime_UTR	Exon 19 of 19	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.*251T>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.*251T>G		3_prime_UTR	Exon 18 of 18	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.*251T>G		3_prime_UTR	Exon 19 of 19	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.*251T>G		3_prime_UTR	Exon 18 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000992 AC: 4 AN: 403070 Hom.: 0 Cov.: 3 AF XY: 0.0000142 AC XY: 3 AN XY: 211446

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

African (AFR) AF: 0.00 AC: 0 AN: 11504

American (AMR) AF: 0.00 AC: 0 AN: 17350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12380

East Asian (EAS) AF: 0.00 AC: 0 AN: 27338

South Asian (SAS) AF: 0.00 AC: 0 AN: 44330

European-Finnish (FIN) AF: 0.0000395 AC: 1 AN: 25316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1776

European-Non Finnish (NFE) AF: 0.00000834 AC: 2 AN: 239702

Other (OTH) AF: 0.0000428 AC: 1 AN: 23374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000300874), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		0.35

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: rs1926220781; hg19: chr22-37461869;