3-194604294-T-A

Variant names:

• chr3-194604294-T-A
• rs777811530
• NM_001011655.3:c.1169A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001011655.3(TMEM44):​c.1169A>T​(p.Asp390Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,578,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D390N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TMEM44 NM_001011655.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

Genes affected

TMEM44 (HGNC:25120): (transmembrane protein 44) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC105374291 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18277621).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011655.3. 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
	TMEM44	NM_001011655.3	MANE Select	c.1169A>T	p.Asp390Val	missense	Exon 9 of 10	NP_001011655.1	Q2T9K0-2
	TMEM44	NM_001166305.2		c.1310A>T	p.Asp437Val	missense	Exon 10 of 11	NP_001159777.1	Q2T9K0-1
	TMEM44	NM_138399.5		c.1169A>T	p.Asp390Val	missense	Exon 9 of 11	NP_612408.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM44	ENST00000347147.9	TSL:1 MANE Select	c.1169A>T	p.Asp390Val	missense	Exon 9 of 10	ENSP00000333355.6	Q2T9K0-2
	TMEM44	ENST00000392432.6	TSL:1	c.1310A>T	p.Asp437Val	missense	Exon 10 of 11	ENSP00000376227.2	Q2T9K0-1
	TMEM44	ENST00000473092.5	TSL:1	c.1169A>T	p.Asp390Val	missense	Exon 9 of 11	ENSP00000418674.1	Q2T9K0-7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000207 AC: 4 AN: 193292 AF XY: 0.0000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000290

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1426508 Hom.: 0 Cov.: 34 AF XY: 0.00000283 AC XY: 2 AN XY: 706500

African (AFR) AF: 0.00 AC: 0 AN: 32578

American (AMR) AF: 0.00 AC: 0 AN: 39392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.000135 AC: 5 AN: 37148

South Asian (SAS) AF: 0.00 AC: 0 AN: 81110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095088

Other (OTH) AF: 0.00 AC: 0 AN: 59080

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74320

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.36		Loss of solvent accessibility (P = 0.0052)
MVP		0.099
MPC		0.19
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.44
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777811530; hg19: chr3-194325023;