chr8-124553087-T-C

Variant names:

• chr8-124553087-T-C
• rs3829037
• NM_014751.6:c.2173A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014751.6(MTSS1):​c.2173A>G​(p.Thr725Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,730 control chromosomes in the GnomAD database, including 39,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3037 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36105 hom.)
• Consequence: MTSS1 NM_014751.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 35 publications found

Genes affected

MTSS1 (HGNC:20443): (MTSS I-BAR domain containing 1) Enables actin monomer binding activity; identical protein binding activity; and signaling receptor binding activity. Predicted to be involved in cellular response to fluid shear stress; negative regulation of epithelial cell proliferation; and urogenital system development. Predicted to act upstream of or within several processes, including actin filament polymerization; adherens junction maintenance; and magnesium ion homeostasis. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

NDUFB9 (HGNC:7704): (NADH:ubiquinone oxidoreductase subunit B9) The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

NDUFB9 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 24

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028086603).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014751.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTSS1	NM_014751.6	MANE Select	c.2173A>G	p.Thr725Ala	missense	Exon 14 of 14	NP_055566.3
	MTSS1	NM_001282971.2		c.2185A>G	p.Thr729Ala	missense	Exon 15 of 15	NP_001269900.1
	MTSS1	NM_001363294.2		c.2170A>G	p.Thr724Ala	missense	Exon 14 of 14	NP_001350223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTSS1	ENST00000518547.6	TSL:1 MANE Select	c.2173A>G	p.Thr725Ala	missense	Exon 14 of 14	ENSP00000429064.1
	MTSS1	ENST00000378017.7	TSL:1	c.2098A>G	p.Thr700Ala	missense	Exon 14 of 14	ENSP00000367256.3
	MTSS1	ENST00000431961.6	TSL:1	c.1327A>G	p.Thr443Ala	missense	Exon 8 of 8	ENSP00000393606.2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29192 AN: 151762 Hom.: 3035 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.196 AC: 49237 AN: 251494 AF XY: 0.199

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.0895

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.219 AC: 319847 AN: 1461850 Hom.: 36105 Cov.: 33 AF XY: 0.217 AC XY: 157997 AN XY: 727232

African (AFR) AF: 0.150 AC: 5030 AN: 33480

American (AMR) AF: 0.0939 AC: 4199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5359 AN: 26136

East Asian (EAS) AF: 0.199 AC: 7913 AN: 39700

South Asian (SAS) AF: 0.164 AC: 14189 AN: 86258

European-Finnish (FIN) AF: 0.303 AC: 16194 AN: 53420

Middle Eastern (MID) AF: 0.249 AC: 1434 AN: 5768

European-Non Finnish (NFE) AF: 0.227 AC: 252795 AN: 1111972

Other (OTH) AF: 0.211 AC: 12734 AN: 60392

GnomAD4 genome AF: 0.192 AC: 29201 AN: 151880 Hom.: 3037 Cov.: 32 AF XY: 0.196 AC XY: 14563 AN XY: 74222

African (AFR) AF: 0.147 AC: 6093 AN: 41422

American (AMR) AF: 0.126 AC: 1921 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 719 AN: 3464

East Asian (EAS) AF: 0.171 AC: 884 AN: 5162

South Asian (SAS) AF: 0.161 AC: 778 AN: 4820

European-Finnish (FIN) AF: 0.308 AC: 3233 AN: 10504

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 14998 AN: 67958

Other (OTH) AF: 0.184 AC: 388 AN: 2106

Alfa AF: 0.209 Hom.: 14818

Bravo AF: 0.179

TwinsUK AF: 0.224 AC: 829

ALSPAC AF: 0.223 AC: 859

ESP6500AA AF: 0.149 AC: 657

ESP6500EA AF: 0.216 AC: 1858

ExAC AF: 0.199 AC: 24215

Asia WGS AF: 0.153 AC: 530 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.0
DANN	Benign	0.44
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N
PhyloP100		0.22
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.097
Sift	Benign	0.80	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.35
ClinPred		0.0018	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.13
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3829037; hg19: chr8-125565328; COSMIC: COSV52674423; COSMIC: COSV52674423;