22-37073551-G-T

Variant names:

• chr22-37073551-G-T
• rs4820268
• NM_001374504.1:c.1536C>A
• TMPRSS6 p.Asp512Glu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3

The NM_001374504.1(TMPRSS6):c.1536C>A (p.Asp512Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,194 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D512N: Likely_pathogenic (ClinVar VariationId 1404, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D512= (synonymous): Benign (ClinVar VariationId 262722, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 1 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D512N: Likely_pathogenic (ClinVar VariationId 1404, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.D512= (synonymous): Benign (ClinVar VariationId 262722, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001374504.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TMPRSS6 NM_001374504.1	MANE Select	c.1536C>A p.Asp512Glu	missense	Exon 13 of 18	Prot: NP_001361433.1 UniProt:
	TMPRSS6 NM_001289000.2		c.1536C>A p.Asp512Glu	missense	Exon 13 of 19	Prot: NP_001275929.1 UniProt:
	TMPRSS6 NM_001289001.2		c.1536C>A p.Asp512Glu	missense	Exon 13 of 18	Prot: NP_001275930.1 UniProt:

TMPRSS6 NM_001374504.1

MANE Select

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: NP_001361433.1UniProt: Q8IU80-1

TMPRSS6 NM_001289000.2

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 19

missense

Prot: NP_001275929.1UniProt: Q8IU80-5

TMPRSS6 NM_001289001.2

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: NP_001275930.1UniProt: Q8IU80-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TMPRSS6 ENST00000676104.1	MANE Select	c.1536C>A p.Asp512Glu	missense	Exon 13 of 18	Prot: ENSP00000501573.1 UniProt:
	TMPRSS6 ENST00000406856.7	TSL:1	c.1536C>A p.Asp512Glu	missense	Exon 13 of 19	Prot: ENSP00000384964.1 UniProt:
	TMPRSS6 ENST00000346753.9	TSL:1	c.1536C>A p.Asp512Glu	missense	Exon 13 of 18	Prot: ENSP00000334962.6 UniProt:

TMPRSS6 ENST00000676104.1

MANE Select

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: ENSP00000501573.1UniProt: Q8IU80-1

TMPRSS6 ENST00000406856.7

TSL:1

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 19

missense

Prot: ENSP00000384964.1UniProt: Q8IU80-5

TMPRSS6 ENST00000346753.9

TSL:1

HGVSc / HGVSpc.1536C>Ap.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: ENSP00000334962.6UniProt: Q8IU80-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461194	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.1
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.14	N
FuncVEP CTI	Pathogenic	0.94
GPN-Star LLR	N/A	-3.8
GPN-Star score	N/A	3.8
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	60/40	polymorphism
MutationAssessor	Pathogenic	3.8	H
PhyloP100	Benign	-1.7
popEVE	Benign	-3.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.91
VESM-3B	Benign	-12

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs4820268;

hg19: chr22-37469591;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar