Genetic Variant NM_014394.3:c.380C>G (chr10-84144913-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014394.3(GHITM):c.380C>G(p.Thr127Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T127I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GHITM
NM_014394.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48

Publications

2 publications found

Variant links:

Genes affected

GHITM (HGNC:17281): (growth hormone inducible transmembrane protein) Involved in inner mitochondrial membrane organization and negative regulation of release of cytochrome c from mitochondria. Located in mitochondrion. Is integral component of mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

GHITM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014394.3. 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
	GHITM	NM_014394.3	MANE Select	c.380C>G	p.Thr127Ser	missense	Exon 5 of 9	NP_055209.2	Q9H3K2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GHITM	ENST00000372134.6	TSL:1 MANE Select	c.380C>G	p.Thr127Ser	missense	Exon 5 of 9	ENSP00000361207.3	Q9H3K2
GHITM	ENST00000897422.1		c.380C>G	p.Thr127Ser	missense	Exon 5 of 9	ENSP00000567481.1
GHITM	ENST00000686247.1		c.380C>G	p.Thr127Ser	missense	Exon 6 of 10	ENSP00000509112.1	Q9H3K2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247068

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000891

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1453414

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.000113

AC:

AN:

44242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

85502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105930

Other (OTH)

AF:

0.00

AC:

AN:

60024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.6

PhyloP100

7.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.47

Sift

Uncertain

0.014

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.89

MutPred

0.78

Loss of catalytic residue at T127 (P = 0.1736)

MVP

0.67

MPC

0.44

ClinPred

0.93

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.86

Mutation Taster

=50/50

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over