17-10725047-C-T

Variant names:

• chr17-10725047-C-T
• rs79737146
• NM_001004313.3:c.251G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001004313.3(TMEM220):​c.251G>A​(p.Arg84His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000709 in 1,614,058 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (14 hom.)
• Consequence: TMEM220 NM_001004313.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.86
• Publications: 3 publications found

Genes affected

TMEM220 (HGNC:33757): (transmembrane protein 220) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003285408).
• BP6: Variant 17-10725047-C-T is Benign according to our data. Variant chr17-10725047-C-T is described in ClinVar as Benign. ClinVar VariationId is 732805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000972 (148/152186) while in subpopulation EAS AF = 0.0222 (115/5182). AF 95% confidence interval is 0.0189. There are 1 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004313.3. 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
	TMEM220	NM_001004313.3	MANE Select	c.251G>A	p.Arg84His	missense	Exon 4 of 6	NP_001004313.1	Q6QAJ8-1
	TMEM220	NM_001359647.2		c.221G>A	p.Arg74His	missense	Exon 3 of 6	NP_001346576.1
	TMEM220	NM_001330139.3		c.221G>A	p.Arg74His	missense	Exon 3 of 5	NP_001317068.1	Q6QAJ8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM220	ENST00000341871.8	TSL:1 MANE Select	c.251G>A	p.Arg84His	missense	Exon 4 of 6	ENSP00000339830.4	Q6QAJ8-1
	TMEM220	ENST00000455996.6	TSL:1	c.221G>A	p.Arg74His	missense	Exon 3 of 5	ENSP00000396973.2	Q6QAJ8-2
	TMEM220	ENST00000857803.1		c.326G>A	p.Arg109His	missense	Exon 5 of 7	ENSP00000527862.1

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152068 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00173 AC: 436 AN: 251484 AF XY: 0.00169

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000682 AC: 997 AN: 1461872 Hom.: 14 Cov.: 31 AF XY: 0.000701 AC XY: 510 AN XY: 727234

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0187 AC: 741 AN: 39698

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111996

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152186 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74416

African (AFR) AF: 0.000241 AC: 10 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68008

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000841 Hom.: 2

Bravo AF: 0.00111

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.014
MPC		0.43
ClinPred		0.0094	T
GERP RS		3.8
PromoterAI		0.14	Neutral
Varity_R		0.027
gMVP		0.079
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs79737146; hg19: chr17-10628364; COSMIC: COSV107401439; COSMIC: COSV107401439;