NM_005491.5:c.156A>G

Variant names:

• chrX-150462831-A-G
• rs16996606
• NM_005491.5:c.156A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005491.5(MAMLD1):​c.156A>G​(p.Pro52Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,206,952 control chromosomes in the GnomAD database, including 47 homozygotes. There are 825 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., 370 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (30 hom. 455 hem.)
• Consequence: MAMLD1 NM_005491.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.138
• Publications: 0 publications found

Genes affected

MAMLD1 (HGNC:2568): (mastermind like domain containing 1) This gene encodes a mastermind-like domain containing protein. This protein may function as a transcriptional co-activator. Mutations in this gene are the cause of X-linked hypospadias type 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

MAMLD1 Gene-Disease associations (from GenCC):

• hypospadias 2, X-linked

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-150462831-A-G is Benign according to our data. Variant chrX-150462831-A-G is described in ClinVar as Benign. ClinVar VariationId is 714971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.138 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1450/112309) while in subpopulation AFR AF = 0.0439 (1354/30874). AF 95% confidence interval is 0.0419. There are 17 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005491.5. 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
	MAMLD1	NM_005491.5	MANE Select	c.156A>G	p.Pro52Pro	synonymous	Exon 3 of 8	NP_005482.2	Q13495-1
	MAMLD1	NM_001400512.1		c.156A>G	p.Pro52Pro	synonymous	Exon 3 of 6	NP_001387441.1	A0A804HKM8
	MAMLD1	NM_001400515.1		c.156A>G	p.Pro52Pro	synonymous	Exon 4 of 9	NP_001387444.1	Q13495-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAMLD1	ENST00000370401.7	TSL:5 MANE Select	c.156A>G	p.Pro52Pro	synonymous	Exon 3 of 8	ENSP00000359428.2	Q13495-1
	MAMLD1	ENST00000426613.5	TSL:1	c.97-6914A>G		intron	N/A	ENSP00000397438.2	Q13495-4
	MAMLD1	ENST00000682016.1		c.156A>G	p.Pro52Pro	synonymous	Exon 4 of 7	ENSP00000507991.1	A0A804HKM8

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1453 AN: 112255 Hom.: 17 Cov.: 23

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000326

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00925

GnomAD2 exomes AF: 0.00392 AC: 711 AN: 181375 AF XY: 0.00227

Gnomad AFR exome AF: 0.0502

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000628

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00269

GnomAD4 exome AF: 0.00156 AC: 1712 AN: 1094643 Hom.: 30 Cov.: 29 AF XY: 0.00126 AC XY: 455 AN XY: 360091

African (AFR) AF: 0.0485 AC: 1278 AN: 26333

American (AMR) AF: 0.00236 AC: 83 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.000241 AC: 13 AN: 54049

European-Finnish (FIN) AF: 0.000815 AC: 33 AN: 40511

Middle Eastern (MID) AF: 0.00176 AC: 7 AN: 3972

European-Non Finnish (NFE) AF: 0.000184 AC: 154 AN: 839089

Other (OTH) AF: 0.00311 AC: 143 AN: 45941

GnomAD4 genome AF: 0.0129 AC: 1450 AN: 112309 Hom.: 17 Cov.: 23 AF XY: 0.0107 AC XY: 370 AN XY: 34475

African (AFR) AF: 0.0439 AC: 1354 AN: 30874

American (AMR) AF: 0.00562 AC: 60 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2684

European-Finnish (FIN) AF: 0.000326 AC: 2 AN: 6132

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.000338 AC: 18 AN: 53269

Other (OTH) AF: 0.00914 AC: 14 AN: 1532

Alfa AF: 0.00738 Hom.: 59

Bravo AF: 0.0153

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.33
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs16996606; hg19: chrX-149631097;