rs60484081

chr22-37069345-CTGGGGTGGGGTGGGGTGGGG-Cchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGchr22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001374504.1(TMPRSS6):c.1842-21_1842-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0000502 in 418,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.94

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.11249481 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 0 (no position change), new splice context is: ctcacctcaccccaccccAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.1842-21_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1842-21_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000110 AC: 1 AN: 90948 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000490

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000408 AC: 3 AN: 73502 Hom.: 0 AF XY: 0.0000700 AC XY: 3 AN XY: 42836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000243

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 20 AN: 327108 Hom.: 0 AF XY: 0.0000765 AC XY: 13 AN XY: 169942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000684

Gnomad4 SAS exome AF: 0.000263

Gnomad4 FIN exome AF: 0.0000435

Gnomad4 NFE exome AF: 0.0000511

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000110 AC: 1 AN: 91020 Hom.: 0 Cov.: 0 AF XY: 0.0000232 AC XY: 1 AN XY: 43052

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000492

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Dec 17, 2022

- -

Iron-refractory iron deficiency anemia Uncertain:1

Uncertain significance, flagged submission

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jun 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385;