3-194633178-T-G

Variant names:

• chr3-194633178-T-G
• rs998707142
• NM_001011655.3:c.38A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001011655.3(TMEM44):​c.38A>C​(p.Asp13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000586 in 1,534,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TMEM44 NM_001011655.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245

Genes affected

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

TMEM44-AS2 (HGNC:41082): (TMEM44 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.091228664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM44	NM_001011655.3	c.38A>C	p.Asp13Ala	missense_variant	Exon 1 of 10	ENST00000347147.9	NP_001011655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM44	ENST00000347147.9	c.38A>C	p.Asp13Ala	missense_variant	Exon 1 of 10	1	NM_001011655.3	ENSP00000333355.6

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151506 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1383406 Hom.: 0 Cov.: 35 AF XY: 0.00000293 AC XY: 2 AN XY: 682388

Gnomad4 AFR exome AF: 0.0000676

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000350

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151506 Hom.: 0 Cov.: 33 AF XY: 0.0000676 AC XY: 5 AN XY: 73984

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38A>C (p.D13A) alteration is located in exon 1 (coding exon 1) of the TMEM44 gene. This alteration results from a A to C substitution at nucleotide position 38, causing the aspartic acid (D) at amino acid position 13 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.0026	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.0090	D;T;T;T
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.93	P;D;B;.
Vest4		0.20
MutPred		0.40		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);
MVP		0.092
MPC		0.13
ClinPred		0.88	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs998707142; hg19: chr3-194353907;