rs4820268

Variant names:

• chr22-37073551-G-A
• rs4820268
• NM_001374504.1:c.1536C>T
• TMPRSS6 p.Asp512Asp

Your query was ambiguous. Multiple possible variants found:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_001374504.1(TMPRSS6):c.1536C>T (p.Asp512Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.539 (AC=869,164) in the gnomAD database across 1,611,200 control chromosomes, including 237,459 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.728. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26621 hom., cov: 32)
  • Exomes 𝑓: 0.53 (210838 hom.)
• Consequence: TMPRSS6 NM_001374504.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (10/10 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7284 — exceeds 5%% threshold (BA1 applied)

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>T p.Asp512Asp	synonymous	Exon 13 of 18	Prot: NP_001361433.1 UniProt:
	TMPRSS6 NM_001289000.2		c.1536C>T p.Asp512Asp	synonymous	Exon 13 of 19	Prot: NP_001275929.1 UniProt:
	TMPRSS6 NM_001289001.2		c.1536C>T p.Asp512Asp	synonymous	Exon 13 of 18	Prot: NP_001275930.1 UniProt:

TMPRSS6 NM_001374504.1

MANE Select

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 18

synonymous

Prot: NP_001361433.1UniProt: Q8IU80-1

TMPRSS6 NM_001289000.2

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 19

synonymous

Prot: NP_001275929.1UniProt: Q8IU80-5

TMPRSS6 NM_001289001.2

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 18

synonymous

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>T p.Asp512Asp	synonymous	Exon 13 of 18	Prot: ENSP00000501573.1 UniProt:
	TMPRSS6 ENST00000406856.7	TSL:1	c.1536C>T p.Asp512Asp	synonymous	Exon 13 of 19	Prot: ENSP00000384964.1 UniProt:
	TMPRSS6 ENST00000346753.9	TSL:1	c.1536C>T p.Asp512Asp	synonymous	Exon 13 of 18	Prot: ENSP00000334962.6 UniProt:

TMPRSS6 ENST00000676104.1

MANE Select

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 18

synonymous

Prot: ENSP00000501573.1UniProt: Q8IU80-1

TMPRSS6 ENST00000406856.7

TSL:1

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 19

synonymous

Prot: ENSP00000384964.1UniProt: Q8IU80-5

TMPRSS6 ENST00000346753.9

TSL:1

HGVSc / HGVSpc.1536C>Tp.Asp512Asp

Exon rankExon 13 of 18

synonymous

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: 0.582	AC:88477	Hom:26588	AN:151916	Cov:32
GnomAD2 exomes	AF: 0.535	AC:134439	Hom:	AN:251322	Cov:
GnomAD4 exome	AF: 0.535	AC:780612	Hom:210838	AN:1459166	Cov:35
GnomAD4 genome	AF: 0.582	AC:88552	Hom:26621	AN:152034	Cov:32
TOPMed (Bravo)	AF: 0.588	AC:155641	Hom:47000	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.553	AC:361890	Hom:102012	AN:654314	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.558	AC:1307	Hom:365	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.467	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.493	AC:148	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.605	AC:7867	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.413	AC:1435	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.500	AC:3618	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.604	AC:1214	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.454	AC:55626	Hom:12799	AN:122510	Cov:
Turkish Variome	AF: 0.479	AC:3204	Hom:787	AN:6686	Cov:
UK10K	AF: 0.526	AC:3977	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.463	AC:4151	Hom:970	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.528 *	5758	10914	0.528 *	9171	17376
BipEx(Bipolar disorder (including schizoaffective))	0.543	15432	28420	0.543	15671	28844
Epi25(Epilepsy)	0.545	22879	41956	0.547	36552	66872
SCHEMA(Schizophrenia)	0.553	84296	152542	0.547	146404	267538

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Iron-refractory iron deficiency anemia (2)
-	-	1	Microcytic anemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0011
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.020
DANN	Benign	0.35
GPN-Star LLR	N/A	2.7
GPN-Star score	N/A	2.7
Mutation Taster	N/A	96/4	polymorphism (auto)
PhyloP100	Benign	-1.7

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.050	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;

COSMIC: COSV60976234;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar