TMPRSS6 p.Asp512Glu

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-37073551-G-C
• chr22-37073551-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_Supporting

The NM_001374504.1(TMPRSS6):c.1536C>G (p.Asp512Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMPRSS6 NM_001374504.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 124 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0); Variant does not impact splicing — splice-hotspot path not applicable

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>G p.Asp512Glu	missense	Exon 13 of 18	Prot: NP_001361433.1 UniProt:
	TMPRSS6 NM_001289000.2		c.1536C>G p.Asp512Glu	missense	Exon 13 of 19	Prot: NP_001275929.1 UniProt:
	TMPRSS6 NM_001289001.2		c.1536C>G p.Asp512Glu	missense	Exon 13 of 18	Prot: NP_001275930.1 UniProt:

TMPRSS6 NM_001374504.1

MANE Select

HGVSc / HGVSpc.1536C>Gp.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: NP_001361433.1UniProt: Q8IU80-1

TMPRSS6 NM_001289000.2

HGVSc / HGVSpc.1536C>Gp.Asp512Glu

Exon rankExon 13 of 19

missense

Prot: NP_001275929.1UniProt: Q8IU80-5

TMPRSS6 NM_001289001.2

HGVSc / HGVSpc.1536C>Gp.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>G p.Asp512Glu	missense	Exon 13 of 18	Prot: ENSP00000501573.1 UniProt:
	TMPRSS6 ENST00000406856.7	TSL:1	c.1536C>G p.Asp512Glu	missense	Exon 13 of 19	Prot: ENSP00000384964.1 UniProt:
	TMPRSS6 ENST00000346753.9	TSL:1	c.1536C>G p.Asp512Glu	missense	Exon 13 of 18	Prot: ENSP00000334962.6 UniProt:

TMPRSS6 ENST00000676104.1

MANE Select

HGVSc / HGVSpc.1536C>Gp.Asp512Glu

Exon rankExon 13 of 18

missense

Prot: ENSP00000501573.1UniProt: Q8IU80-1

TMPRSS6 ENST00000406856.7

TSL:1

HGVSc / HGVSpc.1536C>Gp.Asp512Glu

Exon rankExon 13 of 19

missense

Prot: ENSP00000384964.1UniProt: Q8IU80-5

TMPRSS6 ENST00000346753.9

TSL:1

HGVSc / HGVSpc.1536C>Gp.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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251322	Cov:
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461194	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.000812	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:102012	AN:654314	Cov:

Showing 6 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.8
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	1.7
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
FuncVEP CTI	Pathogenic	0.95
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
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	0.12
Pangolin loss	Benign	0.12	Position offset: -19
SpliceAI score (max)	Benign	0.080	Details are displayed if max score is > 0.2

Showing 3 of 3 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